Pathogenic mechanisms and therapeutic strategies in spinobulbar muscular atrophy.
PDF (553K)
Journal: 2014/August - CNS & neurological disorders drug targets
ISSN: 1996-3181
PUBMED: 24040817
Abstract:
We review the genetic and clinical features of spinobulbar muscular atrophy (SBMA), a progressive neuromuscular disorder caused by a CAG/glutamine tract expansion in the androgen receptor. SBMA was the first polyglutamine disease to be discovered, and we compare and contrast it with related degenerative disorders of the nervous system caused by expanded glutamine tracts. We review the cellular and animals models that have been most widely used to study this disorder, and highlight insights into disease pathogenesis derived from this work. These model systems have revealed critical aspects of the disease, including its hormone dependence, a feature that underlies disease occurrence only in men with the mutant allele. We discuss how this and other findings have been translated to clinical trials for SBMA patients, and examine emerging therapeutic targets that have been identified by recent work.
Open in
PUBMED | PMC | Google Scholar | Wikipedia
Relations:
Content
Citations
(7)
References
(169)
Diseases
(1)
Chemicals
(1)
Organisms
(2)
Processes
(1)
Affiliates
(1)
Similar articles
Articles by the same authors
Discussion board
CNS Neurol Disord Drug Targets 12(8): 1146-1156
PMID: 24040817

Pathogenic mechanisms and therapeutic strategies in spinobulbar muscular atrophy

INTRODUCTION

Spinobulbar muscular atrophy (SBMA) is an inherited, slowly progressive degenerative disease of lower motor neurons and skeletal muscle. Also known as Kennedy’s disease, after the eponymous neurologist William R. Kennedy first described the principal features in 1968, SBMA is characterized clinically by progressive atrophy and weakening of the proximal musculature in the limbs and bulbar distribution [1]. Resulting symptoms include dysarthria, dysphagia, fasciculations, tremor, and gait disturbances [2, 3]. The muscular clinicopathology of SBMA patients is characteristic of lower motor neuron disease with bulk atrophy, flaccid paralysis, hyporeflexia, and fasciculations [4]. Evidence of primary myopathy also exists with painful cramps, weakness, and elevated serum creatine kinase (CK) levels [5]. In addition, SBMA patients commonly exhibit endocrinologic deficits, including gynecomastia, testicular atrophy, and oligospermia [6]. On histopathologic examination, by end stage disease there is marked anterior horn cell loss in both brainstem and spinal cord, and dorsal root ganglia also exhibit a decreased number of sensory neurons [7–9]. Skeletal muscle biopsies show angulated atrophic fibers and fiber type grouping, suggestive of denervation [10]. The prevalence of SBMA is estimated to be at approximately 1 in 400,000, with a proportionally greater number of cases in Japan and Finland, but many patients are likely misdiagnosed due to similar clinical features to amyotrophic lateral sclerosis and other, more common motor neuron diseases [11, 12]. There is currently no established or effective treatment for SBMA.

The occurrence of SBMA through multiple generations of patient families suggested a genetic basis of disease, and the segregation pattern initially indicated an X-linked recessive mode of inheritance [1]. Subsequently, La Spada et al. were the first to identify the causative mutation in 1991, which consists of an expansion of a CAG repeat tract in exon 1 of the androgen receptor (Ar) gene located on the long arm of the X chromosome (Xq11-12) [13]. Of the nine polyglutamine diseases, which include Huntington’s disease, dentatorubropallidoluysian atrophy (DRPLA), and six sub-types of spinocerebellar ataxia (SCA 1, 2, 3, 6, 7, and 17), the causal link between polyglutamine tract expansion and neurodegenerative disease was first established in SBMA. As is characteristic of trinucleotide repeat disorders, SBMA exhibits both CAG-repeat instability and anticipation, or an inverse relationship between tract length versus age of onset and severity of disease [14–19]. Unlike the other polyglutamine diseases, which are inherited in an autosomal dominant fashion and are fully penetrant, SBMA only manifests in male patients while exhibiting little to no disease phenotype in females [14, 20–23]. Although the diminution in disease penetrance in females was initially attributed to lyonization, the identification of subclinical and asymptomatic females homozygous for the mutant allele made this explanation unlikely [19, 22, 24, 25]. Furthermore, although the AR is widely expressed in multiple tissue types, SBMA pathology paradoxically remains isolated within a few distinct cell populations. These observations illustrate two key features of SBMA pathogenesis – hormone dependency and selective cellular vulnerability – which will be further discussed in a later sections.

The causative mutation for SBMA resides in the androgen receptor protein, a Group I steroid hormone nuclear receptor that contains three principal domains: an N-terminal domain (NTD), DNA-binding domain (DBD), and ligand-binding domain (LBD), with a small hinge interregion between the DBD and LBD containing a bipartite nuclear localization sequence [26–29]. The DBD and LBD orchestrate the principle functions of the AR as a steroid hormone receptor. Unbound by ligand, the inactive AR resides bound to chaperone proteins in the cytosol. Upon binding of the LBD by cognate androgens testosterone and dihydrotestosterone (DHT), the AR assembly with the chaperone machinery becomes much more dynamic, the AR homodimerizes and the AR-ligand complex translocates to the nucleus to bind DNA via the DBD, whereupon modulation of genes containing an androgen response element occurs. This mechanism of action allows androgenic hormones to exert masculinizing and trophic effects in target tissues.

Nuanced modulation of these functionalities is accomplished through numerous regulatory elements including short tandem amino acid repeats and sites for post-translational modification. One such element consists of a CAG repeat stretch that encodes a glutamine (Q) tract that is associated with length-dependent modulation of AR function. The polyglutamine tract is highly polymorphic and ranges between 8 and 35 repeats in the general population [30]. Shorter CAG tracts correlate with increased ligand-mediated activation of the AR, while longer tracts, even within the normal range, appear to depress AR activity [31–37]. CAG tracts above a critical threshold length of 38 glutamines result in SBMA, as these expanded polyglutamine stretches promote unfolding of the AR and provide large polar surfaces essential for driving the interaction and aggregation of AR monomers [38, 39]. Surviving lower motor neurons and scrotal skin biopsies from SBMA patients consequently demonstrate nuclear inclusions of aggregated AR with the appropriate histochemical staining [8, 40–42]. Importantly, although AR function is negatively correlated with CAG tract length, a partial loss-of-function mediated by CAG expansion fails to provide adequate explanation for both the androgen insensitivity and neuromuscular pathology seen clinically in SBMA [32, 43–47]. Rather, pathogenic CAG expansion is presumed to confer an additional toxic gain-of-function to the AR, since patients with androgen insensitivity syndrome stemming from AR loss-of-function mutations do not exhibit the neuromuscular pathology of SBMA [48].

Post-translational modifications coordinate additional modulation of AR function. Phosphorylation occurs both in the presence and absence of androgen and directs multiple effects, including regulation of AR conformational changes, localization, and turnover, potentiation of ligand responsiveness and transcriptional activity, and protein-protein interactions [49–54]. Phosphorylation is upregulated in prostate cancer and correlates with increased morbidity and mortality, while negatively modifying toxicity in SBMA [52, 55, 56]. AR acetylation regulates cofactor association, transcriptional activity, and prostate cancer cell growth and survival [57–62]. Modification by small ubiquitin-like modifier (SUMO) occurs at two lysine residues within consensus SUMOylation motifs in the NTD, negatively regulates AR transcriptional activity, and negatively modulates both prostate cancer proliferation and progression and SBMA cytopathology [63–69]. Ubiquitination mediates AR degradation through the ubiquitin-proteasome system or augments AR transactivation, depending on the biological context and E3 ligase involved [70–74]. In SBMA, chaperone-enhanced ubiquitination of the AR increases AR degradation and ameliorates disease (further discussed below) [75].

In addition, the NTD and LBD contain several transcriptional activation function (AF) domains. The NTD contains AF-1, which encompasses residues 142–485 and is necessary for full ligand-dependent transactivation, and AF-5, which encompasses residues 351–528 and is sufficient to act as a ligand-independent, constitutively active transactivational functionality [76–79]. AF-1 coordinates a ligand-dependent intramolecular interaction of the NTD with the C-terminus of the AR via consensus FxxLF/WxxLF motifs (F = phenylalanine, W = tryptophan, x = any amino acid), and this interaction is necessary for AR transactivation in vivo [80–84]. The LBD contains AF-2, which is required for ligand-dependent transcriptional activation [85, 86]. Within AF-2 are leucine-rich motifs with the conserved sequence LxxLL (L = leucine, x = any amino acid) that mediate interactions with AR coactivators [87, 88]. These native functionalities are not only essential for normal AR function but also SBMA pathogenesis, as disruption of these domains significantly attenuates AR aggregation and toxicity [89, 90].

MECHANISMS OF DISEASE

The following sections will discuss the current understanding of SBMA pathophysiology with the requisite background of supporting evidence. Cellular and animal model systems have been developed to study SBMA pathogenesis, which have been instrumental in probing disease mechanisms both unique to SBMA and relevant to neurodegenerative diseases in general.

LIGAND DEPENDENT TOXICITY

As indicated previously, a unique feature of SBMA is the initiation of pathogenesis by androgens, the endogenous ligands of AR. Ligand dependency accounts for the predominant incidence of SBMA in male patients and paucity of disease even in female homozygotes, since females harbor much lower levels of circulating androgens. Furthermore, since key pathogenic events in both SBMA and other proteinopathies are unfolding and aggregation of mutant proteins, and since aspects of these events are concentration-dependent, it follows that compartmentalization of the polyQ AR in the nucleus, mediated by ligand-dependent nuclear translocation, is a critical step in SBMA [91–93].

Among the cellular models of SBMA, the dependence of disease on ligand is well established. In the mouse-rat hybrid glioma-neuroblastoma line NG108-15, in which AR22Q and AR52Q are stably transfected, the androgen-dependent proliferation present in cells expressing wild type AR is abrogated in cells expressing an expanded Q-tract AR [94]. Similarly, transient expression of AR constructs in simian COS-7 cells demonstrates ligand-dependent toxicity and aggregation [95]. Treatment with antiandrogens in the COS-7 model and deletion of the LBD abrogate these effects, and antiandrogens rescue pathologic aggregation of the mutant AR in Neuro2a cells [95, 96]. These findings demonstrate the essential role of ligand binding for fully reproducing SBMA cytopathology. Ligand dependent toxicity is also demonstrable in a PC12 cell model stably transfected with an expanded Q-tract full length AR under the control of a tetracycline-inducible promoter [97]. The glutamine-length appearance of morphologically visible nuclear inclusions, high molecular weight aggregates on Western blot, and cytotoxicity are produced only in the presence of androgen or synthetic androgen analogs. Notably, nuclear translocation per se is not sufficient to initiate pathogenesis, suggesting that ligand binding itself initiates additional conformational changes and cellular processes necessary for pathogenesis [98].

In vivo, the recapitulation of disease occurrence and greater severity in the presence of ligand occurs in both mice (males compared to females) and Drosophila (DHT treatment over vehicle) [91–93, 99–101]. Importantly, the gender limitation in mice occurs only in models expressing a full length androgen receptor, indicating that the truncated version of polyQ AR which does not contain the LBD lacks features of the protein critical for full disease iteration. Additionally, symptoms and pathology comparable to the male phenotype in mice can manifest in females when treated with androgen [91, 101]. Furthermore, prevention of polyQ AR nuclear translocation and amelioration of disease occurs with mutation of the nuclear localization signal or surgical and pharmacologic castration [91, 98, 100, 102]. Together, these data in vivo clearly implicate the essential role of androgens in SBMA and inform efforts to assess androgen-targeted therapy in human clinical trails (see below).

PARTIAL LOSS OF AR FUNCTION

One possible explanation proposed for the loss of AR function phenotype in SBMA, manifested in human patients as androgen insensitivity, is lower expression levels of the expanded Q-tract AR compared to wild type AR. This observation is documented in both SH SY-5Y and MN-1 cell models as well as in vivo [47, 103–105]. Additionally, expansion of the glutamine tract itself intrinsically confers diminution of AR transactivation, as demonstrated by expression assays comparing WT and expanded Q-tract AR in MN-1 cells and AR110Q YAC transgenic mice [47, 106]. Expansion of the glutamine tract also accelerates AR turnover, thereby yielding further decrement in AR function [47]. Notably, testicular abnormalities including disruption of germ cell maturation in AR113Q knock-in male mice reveal toxic effects of the mutant protein, suggesting that phenotypic features such as diminished male fertility may be caused by a mixture of both loss and gain of function conferred by the expanded glutamine tract [107].

TRANSCRIPTIONAL DYSREGULATION

In addition to negative effects on the intrinsic transactivational capacity of the AR, aberrant cofactor interaction has been proposed as a mechanism mediating a toxic gain of function of the expanded Q-tract AR. One key observation in MN-1 cells, mouse, and Drosophila models of SBMA is the co-localization of transcription factors, including CREB binding protein (CBP), in nuclear inclusions of the mutant AR, suggesting that cytotoxicity stems in part from abnormal interaction with and sequestration of transcription factors leading to dysregulation of gene expression, including that of vascular endothelial growth factor (VEGF) and transforming growth factor β (TGFβ) receptor type II [93, 108–111]. Analogously, these pathologic changes are shown to occur in other polyglutamine diseases [112, 113]. Interestingly, CBP and several other inclusion interactors also contain polyglutamine tracts, which may facilitate AR-cofactor association.

It has therefore been hypothesized that accumulution of these factors and other critical regulators in nuclear inclusions results in a depletion of their availability, thereby compromising their functions in transcription. In line with this model of pathogenesis, treatment of cell and animal models with HDAC inhibitors and overexpression of CBP in a Drosophila model of polyglutamine disease significantly improves transcriptional aberrancies and rescues cell death in vitro, ommatidial degeneration in Drosophila, and improves both survival and motor performance in SBMA mice [108, 114–116].

INCLUSIONS ARE NOT PRIMARY MEDIATORS OF TOXICITY

Neuronal intranuclear inclusions (NII), defined as proteinaceous aggregates made visible on histopathology with the appropriate staining, are a pathognomonic feature of SBMA, contain at least a portion of the polyQ AR, and are found in lower motor neurons and scrotal skin cells of SBMA patients [8, 40–42]. These inclusions are similar to those identified in other polyQ disorders and their role in disease pathogenesis is similarly controversial. In model systems of SBMA, as in other polyQ diseases, these large nuclear inclusions do not always correlate with cell death. Rather, pathology is better correlated with the occurrence of microaggregates, or soluble intermediates of aggregated and unfolded mutant proteins that are isolated biochemically [117–120]. Specifically, glutamine-length dependent toxicity can be demonstrated in the SH SY-5Y model of SBMA without aggregate formation [103]. Moreover, toxicity correlates with microaggregates in the inducible PC12 cell model of SBMA as well as Sf9 cells and Drosophila [97, 121].

Additional studies further dissociate toxicity from AR inclusions. Treatment of HEK293, PC12, and Drosophila models of SBMA with the compound B2 promotes inclusion formation and reduce toxicity [122]. In HEK293 and MN-1 cells, expansion of the AR glutamine tract promotes its incorporation in the formation of aggresomes, which are large juxtanuclear structures similar to intranuclear inclusions [123]. Aggresomes and inclusions may represent a cellular adaptive response to mutant AR and other aggregated proteins, since their formation correlates with cell survival and their disruption exacerbates cytotoxicity [124]. These results lend further support to the notion that aggregates are end-stage, protective structures rather than the primary toxic entity.

AR FRAGMENTS ARE TOXIC

The sole detection of AR amino-terminal epitopes within nuclear inclusions from SBMA patient tissue suggested that these aggregates are composed of a proteolytic byproduct of the AR protein that includes the expanded glutamine tract [40, 41]. Pathogenic proteolysis of the AR occurs in a caspase-dependent manner in vitro, in line with proteolytic processing seen in other polyglutamine disease models [44, 125–136]. Although expression of truncated polyQ AR fragments in cell and Drosophila models confers toxicity in a glutamine-length dependent manner, expression of amino-terminal truncated fragments in mice causes toxicity that does not exhibit the gender delimitation or cell-type specificity of SBMA [109, 137, 138]. Taken together, these studies indicate that, although protein cleavage is likely a component of the disease process that generates a toxic protein fragment, model systems based on expression of these fragments do not reproduce important aspects of the SBMA phenotype.

CHAPERONES AND AR PROTEOSTASIS

Heat shock proteins are essential regulators of protein folding, function, and stability. For the AR, the heat shock protein 90 (Hsp90)-based chaperone machinery serves to modulate ligand affinity, ligand-dependent conformational changes, and nuclear trafficking following ligand binding. In this machinery, association with Hsp90 stabilizes the AR, whereas proteasomal degradation of the unfolded receptor is regulated by Hsp70 and its co-chaperones through the recruitment of chaperone dependent E3 ubiqutin ligases including CHIP (C-terminal Hsp70-interacting protein) [72–74, 139–143]. Multiple studies indicate the involvement of these chaperones in SBMA pathogenesis. Components of the Hsp70/90 machinery co-localize in mutant AR aggregates, suggesting abnormal seqestration of these chaperones and raising the possibility of dysregulation of chaperone-mediated proteostasis [109, 144]. Conversely, overexpression of Hsp70 or pharmacological inhibition of Hsp90 increases AR degradation and amelioriates disease phenotype in cellular and mouse models of SBMA; similar beneficial effects in SBMA mice are observed following overexpression of CHIP [75, 145–147]. Administration of 17-diethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) and 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), which are derivatives of geldanamycin and inhibitors of Hsp90, promote degradation of the AR and improve motor performance in AR97Q transgenic mice [148, 149]. Together, these studies establish that inhibition of Hsp90 or activation of Hsp70-dependent ubiquitination are viable therapeutic targets for trial in SBMA patients.

MULTIPLE DOWNSTREAM PATHWAYS ARE TARGETED BY POLYQ AR

In addition to causing transcriptional and proteostatic dysregulation, the toxic gain of function conferred by the expanded glutamine tract disrupts a large number of downstream pathways that are critical for cell survival (Figure 1). Hormone and glutamine length dependent changes in RNA processing have been demonstrated in SBMA knock-in mice, indicating that both transcriptional and post-transcriptional regulation of gene expression is altered in disease [150]. Additionally, multiple cytosolic targets of toxicity have been identified. MN-1 cells expressing AR65Q demonstrate marked mitochondrial pathology, increased activation of the intrinsic apoptosis pathway, and dysregulation of nuclear-mediated mitochondrial gene expression through PGC-1 (peroxisome proliferator-activated receptor gamma coactivator 1) suppression, while antioxidant treatments rescue toxicity [136, 151]. Together, these studies suggest that expansion of the AR glutamine tract promotes mitochondrial dysfunction and provides a direct causal link between transcriptional abberance and mitochondrial pathology. The unfolded protein response is significantly upregulated in SBMA cell models and in AR113Q knock-in mice, and genetic deletion of the ER stress-dependent transcription factor CHOP (C/EBP homologous protein) exacerbates disease phenotype, thereby implicating a role of ER stress in SBMA [152, 153]. The polyQ AR has also been shown to compromise retrograde axonal transport, an effect that may contribute to lower motor neuron degneration [154–157]. While cell-autonomous toxicity within vulnerable cell populations may be mediated by abnormal protein interactions (see above), there is also evidence that toxic effects arising in skeletal muscle initiate non-cell-autonomous degeneration of lower motor neurons, perhaps by impairing trophic support [52, 101, 158–161]. Taken together, these studies indicate that mutliple downstream pathways are disrupted by the polyQ AR. As no single pathway has emerged as a critical mediator of pathogenesis, we suggest that therapeutic strategies targeting the mutant protein may be most effective in modifying the course of disease.

An external file that holds a picture, illustration, etc. Object name is nihms572701f1.jpg
Spinobulbar muscular atrophy disrupts multiple cellular pathways

Expansion of the polyglutamine tract in the NTD of the androgen receptor (denoted by series of Qs) beyond 38 CAG repeats promotes AR unfolding and is necessary but not sufficient for development of SBMA. (a) Binding of polyQ AR to cognate ligands testosterone and DHT drives the conformational changes and nuclear localization of the mutant protein required for full pathogenesis. (b) Reduction of transactivation function leads to disruption of androgen-responsive gene expression and (c) transcriptional dysregulation, which in turn contribute to the phenotype of androgen insensitivity in SBMA patients. (d) Proteolysis of the polyQ AR, which may be caspase-mediated, generates toxic, N-terminal fragments of the mutant protein that ultimately oligomerize and aggregate in nuclear inclusions. (e) These inclusions contain accumulations of transcriptional cofactors (such as CBP), molecular chaperones (such as Hsp70/90 complexes), and splicing machinery, the depletions of which further disrupt vital (c) transcriptional and proteostatic processes and (f) RNA splicing. Selectively vulnerable cell populations in SBMA experience additional toxic insults, including (g) mitochondrial pathology, (h) ER stress, and (i) disruption of retrograde axonal transport. AR, androgen receptor; polyQ, polyglutamine; ARE, androgen response element; VEGF, vascular endothelial growth factor; TGFβR-II, transforming growth factor β receptor type II; CBP, CREB binding protein; snRNP, small nuclear ribonucleoprotein.

CLINICAL TRIALS

The understanding of disease mechanisms gleaned from cell and animal models have provided the basis for several clinical trials to date.

To address the ligand-dependency of SBMA, administration of leuprorelin acetate, which is a partial agonist of gonadotropin releasing hormone and a potent suppressor of testosterone release, rescued disease in AR97Q mice [91, 102]. These results were translated into a phase 2 trial for the use of leuprorelin in SBMA patients [162, 163]. Leuprorelin treatment for 48 weeks did not significantly improve the primary outcome measure of scores on the Revised ALS Functional Rating Scale (ALSFRS-R), nor did serum CK levels decrease. Several secondary outcomes showed significant rescue, including measures of cricopharyngeal function and nuclear inclusions on scrotal skin biopsy. Furthermore, in a open label follow-up, all of these measures except serum CK saw significant improvement after 96 weeks.

These encouraging findings were followed by the phase 3 trial known as the Japan SBMA Interventional Trial for TAP-144-SR (JASMITT). In this larger study, the leurprorelin group saw no significant improvements in cricopharyngeal function or ALSFRS-R scores, although there were significant reductions in some secondary measures, such as polyglutamine positive cells in scrotal skin biopsies and serum CK levels. In a separate trial, administration of dutasteride, which inhibits 5α-reductase and thus enzymatic conversion of testosterone to the more potent androgen DHT, similarly found no significant improvement in primary endpoints [164].

The equivocal findings of androgen-targeted therapies in humans highlight difficulties in treating a slowly progressive disease where clinical severity may vary depending on CAG repeat length or other genetic and environmental factors. Though anti-androgens displayed promise for slowing disease progression, these trials also raised the possibility that intervention early in the disease course may be most effective. In these studies, the average disease duration in trial patients at the time of enrollment ranged from 10.8 to 13.3 years [162–164]; whether patients earlier in the course of disease are more responsive to therapeutic intervention is an important unanswered question. This work also revealed the urgent need for further studies to better understand the natural history of SBMA and to develop sensitive surrogate markers that will facilitate long term follow-up in future trials.

An important, unresolved question for SBMA patients is whether excercise is beneficial. Currently, there is one two-year clinical trial underway to assess the efficacy of functional exercise and stretching (Trial Number 11-N-0171; {"type":"clinical-trial","attrs":{"text":"NCT01369901","term_id":"NCT01369901"}}NCT01369901). The results of this study will be informative about applicability of exercise to SBMA therapy, as the benefit or harm of exercise is not well established in this disease or other neuromuscular disorders [165–168]. Future clinical trial candidates include ASC-J9, a disruptor of AR-coregulator interactions and promoter of AR/aggregate clearance, and insulin-like growth factor 1 (IGF-1), both of which have been shown to improve disease phenotype in vitro and in vivo [158, 169]. Both agents require further study in preclinical models before advancing to clinical trial.

CONCLUSIONS & FUTURE DIRECTIONS

The number of pathogenic mechanisms implicated in SBMA is demonstrative of the complexity inherent in this polyglutamine disorder and presents many challenges to solving critical scientific and therapeutic questions. Despite the pathophysiological intricacy of SBMA, it is important to note that the variety of cellular processes disrupted share a common initiatory stimulus in the form of the polyQ AR; it therefore follows that pursuing and optimizing therapeutic strategies targeting the polyQ AR in particular would prove most beneficial in ameliorating disease vis-à-vis targeting the multiple downstream sequelae. In particular, the clinical shortcomings to date of using ligand-based therapies may be overcome if used in combination with other strategies, such as chaperone directed, to potentiate their AR-targeted effects. Additionally, recent evidence suggests that the polyQ AR may be an autophagic substrate when it is localized to the cytoplasm [98, 170], but the extent to which autophagy activators will alleviate disease in vivo remains unclear [152].

Furthermore, traditional clinical measures used to assess disease status in other neuromuscular diseases suffer from inadequate applicability in SBMA trials due to marked variability of these measures among SBMA patients, poor sensitivity, and a dearth of established clinical reliability. Future trials would most benefit from primary endpoints defined by reliable outcome measures that more accurately reflect disease progression, patient self-assessments, and therapeutic efficacy. Trial design might also benefit from longer duration, earlier initiation of interventions and greater enrollment of patients. These parameters, unfortunately, are limited by the small patient population available for this rare disorder and the poor diagnostic sensitivity for SBMA. Subsequent research following promising leads into overcoming these clinical and therapeutic challenges and further disentangling SBMA pathogenesis will improve quality of care and address disease mechanisms common to SBMA and other neurodegenerative disorders.

Acknowledgments

The authors’ work is supported by grants from the NIH (NS055746 to APL, and NS076189 to JPC).

Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA 48109
Medical Scientist Training Program, University of Michigan Medical School, Ann Arbor, Michigan, USA 48109
Address correspondence to: Andrew Lieberman, Department of Pathology, University of Michigan Medical School, 3510 MSRB1, 1150 W. Medical Center Dr., Ann Arbor, Michigan 48109-0605, Telephone: (734) 647-4624, Fax: (734) 615-3441, ude.hcimu@nmrebeil
Copyright notice

Abstract

We review the genetic and clinical features of spinobulbar muscular atrophy (SBMA), a progressive neuromuscular disorder caused by a CAG/glutamine tract expansion in the androgen receptor. SBMA was the first polyglutamine disease to be discovered, and we compare and contrast it with related degenerative disorders of the nervous system caused by expanded glutamine tracts. We review the cellular and animals models that have been most widely used to study this disorder, and highlight insights into disease pathogenesis derived from this work. These model systems have revealed critical aspects of the disease, including its hormone dependence, a feature that underlies disease occurrence only in men with the mutant allele. We discuss how this and other findings have been translated to clinical trials for SBMA patients, and examine emerging therapeutic targets that have been identified by recent work.

Keywords: androgen receptor, anti-androgen, CAG/polyglutamine disorder, motor neuron disease, protein aggregation, spinobulbar muscular atrophy (SBMA)
Abstract

Footnotes

CONFLICT OF INTEREST

None.

Footnotes

References

  • 1. Kennedy WR, Alter M, Sung JH. Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait. Neurology. 1968;18(7):671–80.[PubMed]
  • 2. Sperfeld AD, Karitzky J, Brummer D, Schreiber H, Haussler J, Ludolph AC, Hanemann COX-linked bulbospinal neuronopathy: Kennedy disease. Arch Neurol. 2002;59(12):1921–6.[PubMed][Google Scholar]
  • 3. Katsuno M, Adachi H, Tanaka F, Sobue GSpinal and bulbar muscular atrophy: ligand-dependent pathogenesis and therapeutic perspectives. J Mol Med (Berl) 2004;82(5):298–307.[PubMed][Google Scholar]
  • 4. Ferrante MA, Wilbourn AJThe characteristic electrodiagnostic features of Kennedy’s disease. Muscle Nerve. 1997;20(3):323–9.[PubMed][Google Scholar]
  • 5. Chahin N, Sorenson EJSerum creatine kinase levels in spinobulbar muscular atrophy and amyotrophic lateral sclerosis. Muscle Nerve. 2009;40(1):126–9.[PubMed][Google Scholar]
  • 6. Dejager S, Bry-Gauillard H, Bruckert E, Eymard B, Salachas F, LeGuern E, Tardieu S, Chadarevian R, Giral P, Turpin GA comprehensive endocrine description of Kennedy’s disease revealing androgen insensitivity linked to CAG repeat length. J Clin Endocrinol Metab. 2002;87(8):3893–901.[PubMed][Google Scholar]
  • 7. Antonini G, Gragnani F, Romaniello A, Pennisi EM, Morino S, Ceschin V, Santoro L, Cruccu GSensory involvement in spinal-bulbar muscular atrophy (Kennedy’s disease) Muscle Nerve. 2000;23(2):252–8.[PubMed][Google Scholar]
  • 8. Adachi H, Katsuno M, Minamiyama M, Waza M, Sang C, Nakagomi Y, Kobayashi Y, Tanaka F, Doyu M, Inukai A, Yoshida M, Hashizume Y, Sobue GWidespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients. Brain. 2005;128(Pt 3):659–70.[PubMed][Google Scholar]
  • 9. Suzuki K, Katsuno M, Banno H, Takeuchi Y, Atsuta N, Ito M, Watanabe H, Yamashita F, Hori N, Nakamura T, Hirayama M, Tanaka F, Sobue GCAG repeat size correlates to electrophysiological motor and sensory phenotypes in SBMA. Brain. 2008;131(Pt 1):229–39.[PubMed][Google Scholar]
  • 10. Soraru G, D’Ascenzo C, Polo A, Palmieri A, Baggio L, Vergani L, Gellera C, Moretto G, Pegoraro E, Angelini CSpinal and bulbar muscular atrophy: skeletal muscle pathology in male patients and heterozygous females. J Neurol Sci. 2008;264(1–2):100–5.[PubMed][Google Scholar]
  • 11. Parboosingh JS, Figlewicz DA, Krizus A, Meininger V, Azad NA, Newman DS, Rouleau GASpinobulbar muscular atrophy can mimic ALS: the importance of genetic testing in male patients with atypical ALS. Neurology. 1997;49(2):568–72.[PubMed][Google Scholar]
  • 12. Hama T, Hirayama M, Hara T, Nakamura T, Atsuta N, Banno H, Suzuki K, Katsuno M, Tanaka F, Sobue GDiscrimination of spinal and bulbar muscular atrophy from amyotrophic lateral sclerosis using sensory nerve action potentials. Muscle Nerve. 2012;45(2):169–74.[PubMed][Google Scholar]
  • 13. La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KHAndrogen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. 1991;352(6330):77–9.[PubMed][Google Scholar]
  • 14. La Spada AR, Roling DB, Harding AE, Warner CL, Spiegel R, Hausmanowa-Petrusewicz I, Yee WC, Fischbeck KHMeiotic stability and genotype-phenotype correlation of the trinucleotide repeat in X-linked spinal and bulbar muscular atrophy. Nat Genet. 1992;2(4):301–4.[PubMed][Google Scholar]
  • 15. Doyu M, Sobue G, Mukai E, Kachi T, Yasuda T, Mitsuma T, Takahashi ASeverity of X-linked recessive bulbospinal neuronopathy correlates with size of the tandem CAG repeat in androgen receptor gene. Ann Neurol. 1992;32(5):707–10.[PubMed][Google Scholar]
  • 16. Amato AA, Prior TW, Barohn RJ, Snyder P, Papp A, Mendell JRKennedy’s disease: a clinicopathologic correlation with mutations in the androgen receptor gene. Neurology. 1993;43(4):791–4.[PubMed][Google Scholar]
  • 17. Sobue G, Doyu M, Morishima T, Mukai E, Yasuda T, Kachi T, Mitsuma TAberrant androgen action and increased size of tandem CAG repeat in androgen receptor gene in X-linked recessive bulbospinal neuronopathy. J Neurol Sci. 1994;121(2):167–71.[PubMed][Google Scholar]
  • 18. Shimada N, Sobue G, Doyu M, Yamamoto K, Yasuda T, Mukai E, Kachi T, Mitsuma TX-linked recessive bulbospinal neuronopathy: clinical phenotypes and CAG repeat size in androgen receptor gene. Muscle Nerve. 1995;18(12):1378–84.[PubMed][Google Scholar]
  • 19. Mariotti C, Castellotti B, Pareyson D, Testa D, Eoli M, Antozzi C, Silani V, Marconi R, Tezzon F, Siciliano G, Marchini C, Gellera C, Donato SDPhenotypic manifestations associated with CAG-repeat expansion in the androgen receptor gene in male patients and heterozygous females: a clinical and molecular study of 30 families. Neuromuscul Disord. 2000;10(6):391–7.[PubMed][Google Scholar]
  • 20. Karaer H, Kaplan Y, Kurt S, Gundogdu A, Erdogan B, Basak NAPhenotypic differences in a large family with Kennedy’s disease from the Middle Black Sea region of Turkey. Amyotroph Lateral Scler. 2010;11(1–2):148–53.[PubMed][Google Scholar]
  • 21. Sobue G, Doyu M, Kachi T, Yasuda T, Mukai E, Kumagai T, Mitsuma TSubclinical phenotypic expressions in heterozygous females of X-linked recessive bulbospinal neuronopathy. J Neurol Sci. 1993;117(1–2):74–8.[PubMed][Google Scholar]
  • 22. Ishihara H, Kanda F, Nishio H, Sumino K, Chihara KClinical features and skewed X-chromosome inactivation in female carriers of X-linked recessive spinal and bulbar muscular atrophy. J Neurol. 2001;248(10):856–60.[PubMed][Google Scholar]
  • 23. Greenland KJ, Beilin J, Castro J, Varghese PN, Zajac JDPolymorphic CAG repeat length in the androgen receptor gene and association with neurodegeneration in a heterozygous female carrier of Kennedy’s disease. J Neurol. 2004;251(1):35–41.[PubMed][Google Scholar]
  • 24. Kristiansen M, Knudsen GP, Tanner SM, McEntagart M, Jungbluth H, Muntoni F, Sewry C, Gallati S, Orstavik KH, Wallgren-Pettersson CX-inactivation patterns in carriers of X-linked myotubular myopathy. Neuromuscul Disord. 2003;13(6):468–71.[PubMed][Google Scholar]
  • 25. Schmidt BJ, Greenberg CR, Allingham-Hawkins DJ, Spriggs ELExpression of X-linked bulbospinal muscular atrophy (Kennedy disease) in two homozygous women. Neurology. 2002;59(5):770–2.[PubMed][Google Scholar]
  • 26. Jenster G, van der Korput HA, van Vroonhoven C, van der Kwast TH, Trapman J, Brinkmann AODomains of the human androgen receptor involved in steroid binding, transcriptional activation, and subcellular localization. Mol Endocrinol. 1991;5(10):1396–404.[PubMed][Google Scholar]
  • 27. Hiipakka RA, Liao SMolecular Mechanism of Androgen Action. Trends in Endocrinology & Metabolism. 1998;9(8):317–324.[PubMed][Google Scholar]
  • 28. MacLean HE, Warne GL, Zajac JDLocalization of functional domains in the androgen receptor. J Steroid Biochem Mol Biol. 1997;62(4):233–42.[PubMed][Google Scholar]
  • 29. McEwan IJMolecular mechanisms of androgen receptor-mediated gene regulation: structure-function analysis of the AF-1 domain. Endocr Relat Cancer. 2004;11(2):281–93.[PubMed][Google Scholar]
  • 30. Rajender S, Singh L, Thangaraj KPhenotypic heterogeneity of mutations in androgen receptor gene. Asian J Androl. 2007;9(2):147–79.[PubMed][Google Scholar]
  • 31. Beilin J, Ball EM, Favaloro JM, Zajac JDEffect of the androgen receptor CAG repeat polymorphism on transcriptional activity: specificity in prostate and non-prostate cell lines. J Mol Endocrinol. 2000;25(1):85–96.[PubMed][Google Scholar]
  • 32. Chamberlain NL, Driver ED, Miesfeld RLThe length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res. 1994;22(15):3181–6.[Google Scholar]
  • 33. Tut TG, Ghadessy FJ, Trifiro MA, Pinsky L, Yong ELLong polyglutamine tracts in the androgen receptor are associated with reduced trans-activation, impaired sperm production, and male infertility. J Clin Endocrinol Metab. 1997;82(11):3777–82.[PubMed][Google Scholar]
  • 34. Buchanan G, Yang M, Cheong A, Harris JM, Irvine RA, Lambert PF, Moore NL, Raynor M, Neufing PJ, Coetzee GA, Tilley WDStructural and functional consequences of glutamine tract variation in the androgen receptor. Hum Mol Genet. 2004;13(16):1677–92.[PubMed][Google Scholar]
  • 35. Irvine RA, Ma H, Yu MC, Ross RK, Stallcup MR, Coetzee GAInhibition of p160-mediated coactivation with increasing androgen receptor polyglutamine length. Hum Mol Genet. 2000;9(2):267–74.[PubMed][Google Scholar]
  • 36. Mhatre AN, Trifiro MA, Kaufman M, Kazemi-Esfarjani P, Figlewicz D, Rouleau G, Pinsky LReduced transcriptional regulatory competence of the androgen receptor in X-linked spinal and bulbar muscular atrophy. Nat Genet. 1993;5(2):184–8.[PubMed][Google Scholar]
  • 37. Watson PA, Chen YF, Balbas MD, Wongvipat J, Socci ND, Viale A, Kim K, Sawyers CLConstitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor. Proc Natl Acad Sci U S A. 2010;107(39):16759–65.[Google Scholar]
  • 38. Tanaka M, Morishima I, Akagi T, Hashikawa T, Nukina NIntra- and intermolecular beta-pleated sheet formation in glutamine-repeat inserted myoglobin as a model for polyglutamine diseases. J Biol Chem. 2001;276(48):45470–5.[PubMed][Google Scholar]
  • 39. Rusmini P, Sau D, Crippa V, Palazzolo I, Simonini F, Onesto E, Martini L, Poletti AAggregation and proteasome: the case of elongated polyglutamine aggregation in spinal and bulbar muscular atrophy. Neurobiol Aging. 2007;28(7):1099–111.[PubMed][Google Scholar]
  • 40. Li M, Miwa S, Kobayashi Y, Merry DE, Yamamoto M, Tanaka F, Doyu M, Hashizume Y, Fischbeck KH, Sobue GNuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy. Ann Neurol. 1998;44(2):249–54.[PubMed][Google Scholar]
  • 41. Li M, Nakagomi Y, Kobayashi Y, Merry DE, Tanaka F, Doyu M, Mitsuma T, Hashizume Y, Fischbeck KH, Sobue GNonneural nuclear inclusions of androgen receptor protein in spinal and bulbar muscular atrophy. Am J Pathol. 1998;153(3):695–701.[Google Scholar]
  • 42. Banno H, Adachi H, Katsuno M, Suzuki K, Atsuta N, Watanabe H, Tanaka F, Doyu M, Sobue GMutant androgen receptor accumulation in spinal and bulbar muscular atrophy scrotal skin: a pathogenic marker. Ann Neurol. 2006;59(3):520–6.[PubMed][Google Scholar]
  • 43. Nakajima H, Kimura F, Nakagawa T, Furutama D, Shinoda K, Shimizu A, Ohsawa NTranscriptional activation by the androgen receptor in X-linked spinal and bulbar muscular atrophy. J Neurol Sci. 1996;142(1–2):12–6.[PubMed][Google Scholar]
  • 44. Merry DE, Kobayashi Y, Bailey CK, Taye AA, Fischbeck KHCleavage, aggregation and toxicity of the expanded androgen receptor in spinal and bulbar muscular atrophy. Hum Mol Genet. 1998;7(4):693–701.[PubMed][Google Scholar]
  • 45. Fischbeck KH, Lieberman A, Bailey CK, Abel A, Merry DEAndrogen receptor mutation in Kennedy’s disease. Philos Trans R Soc Lond B Biol Sci. 1999;354(1386):1075–8.[Google Scholar]
  • 46. Kazemi-Esfarjani P, Trifiro MA, Pinsky LEvidence for a repressive function of the long polyglutamine tract in the human androgen receptor: possible pathogenetic relevance for the (CAG)n-expanded neuronopathies. Hum Mol Genet. 1995;4(4):523–7.[PubMed][Google Scholar]
  • 47. Lieberman AP, Harmison G, Strand AD, Olson JM, Fischbeck KHAltered transcriptional regulation in cells expressing the expanded polyglutamine androgen receptor. Hum Mol Genet. 2002;11(17):1967–76.[PubMed][Google Scholar]
  • 48. Brinkmann AOMolecular basis of androgen insensitivity. Mol Cell Endocrinol. 2001;179(1–2):105–9.[PubMed][Google Scholar]
  • 49. Gioeli DSignal transduction in prostate cancer progression. Clin Sci (Lond) 2005;108(4):293–308.[PubMed][Google Scholar]
  • 50. Gioeli D, Black BE, Gordon V, Spencer A, Kesler CT, Eblen ST, Paschal BM, Weber MJStress kinase signaling regulates androgen receptor phosphorylation, transcription, and localization. Mol Endocrinol. 2006;20(3):503–15.[PubMed][Google Scholar]
  • 51. Kraus S, Gioeli D, Vomastek T, Gordon V, Weber MJReceptor for activated C kinase 1 (RACK1) and Src regulate the tyrosine phosphorylation and function of the androgen receptor. Cancer Res. 2006;66(22):11047–54.[PubMed][Google Scholar]
  • 52. Palazzolo I, Burnett BG, Young JE, Brenne PL, La Spada AR, Fischbeck KH, Howell BW, Pennuto MAkt blocks ligand binding and protects against expanded polyglutamine androgen receptor toxicity. Hum Mol Genet. 2007;16(13):1593–603.[PubMed][Google Scholar]
  • 53. Ponguta LA, Gregory CW, French FS, Wilson EMSite-specific androgen receptor serine phosphorylation linked to epidermal growth factor-dependent growth of castration-recurrent prostate cancer. J Biol Chem. 2008;283(30):20989–1001.[Google Scholar]
  • 54. Gordon V, Bhadel S, Wunderlich W, Zhang J, Ficarro SB, Mollah SA, Shabanowitz J, Hunt DF, Xenarios I, Hahn WC, Conaway M, Carey MF, Gioeli DCDK9 regulates AR promoter selectivity and cell growth through serine 81 phosphorylation. Mol Endocrinol. 2010;24(12):2267–80.[Google Scholar]
  • 55. Liao Y, Grobholz R, Abel U, Trojan L, Michel MS, Angel P, Mayer DIncrease of AKT/PKB expression correlates with gleason pattern in human prostate cancer. Int J Cancer. 2003;107(4):676–80.[PubMed][Google Scholar]
  • 56. McCall P, Gemmell LK, Mukherjee R, Bartlett JM, Edwards JPhosphorylation of the androgen receptor is associated with reduced survival in hormone-refractory prostate cancer patients. Br J Cancer. 2008;98(6):1094–101.[Google Scholar]
  • 57. Fu M, Wang C, Wang J, Zhang X, Sakamaki T, Yeung YG, Chang C, Hopp T, Fuqua SA, Jaffray E, Hay RT, Palvimo JJ, Janne OA, Pestell RGAndrogen receptor acetylation governs trans activation and MEKK1-induced apoptosis without affecting in vitro sumoylation and trans-repression function. Mol Cell Biol. 2002;22(10):3373–88.[Google Scholar]
  • 58. Gaughan L, I, Logan R, Cook S, Neal DE, Robson CNTip60 and histone deacetylase 1 regulate androgen receptor activity through changes to the acetylation status of the receptor. J Biol Chem. 2002;277(29):25904–13.[PubMed][Google Scholar]
  • 59. Fu M, Rao M, Wang C, Sakamaki T, Wang J, Di Vizio D, Zhang X, Albanese C, Balk S, Chang C, Fan S, Rosen E, Palvimo JJ, Janne OA, Muratoglu S, Avantaggiati ML, Pestell RGAcetylation of androgen receptor enhances coactivator binding and promotes prostate cancer cell growth. Mol Cell Biol. 2003;23(23):8563–75.[Google Scholar]
  • 60. Fu M, Liu M, Sauve AA, Jiao X, Zhang X, Wu X, Powell MJ, Yang T, Gu W, Avantaggiati ML, Pattabiraman N, Pestell TG, Wang F, Quong AA, Wang C, Pestell RGHormonal control of androgen receptor function through SIRT1. Mol Cell Biol. 2006;26(21):8122–35.[Google Scholar]
  • 61. Gong J, Zhu J, Goodman OB, Jr, Pestell RG, Schlegel PN, Nanus DM, Shen RActivation of p300 histone acetyltransferase activity and acetylation of the androgen receptor by bombesin in prostate cancer cells. Oncogene. 2006;25(14):2011–21.[PubMed][Google Scholar]
  • 62. Montie HL, Pestell RG, Merry DESIRT1 modulates aggregation and toxicity through deacetylation of the androgen receptor in cell models of SBMA. J Neurosci. 2011;31(48):17425–36.[Google Scholar]
  • 63. Poukka H, Karvonen U, Janne OA, Palvimo JJCovalent modification of the androgen receptor by small ubiquitin-like modifier 1 (SUMO-1) Proc Natl Acad Sci U S A. 2000;97(26):14145–50.[Google Scholar]
  • 64. Kaikkonen S, Jääskeläinen T, Karvonen U, Rytinki MM, Makkonen H, Gioeli D, Paschal BM, Palvimo JJSUMO-specific protease 1 (SENP1) reverses the hormone-augmented SUMOylation of androgen receptor and modulates gene responses in prostate cancer cells. Molecular Endocrinology. 2009;23(3):292–307.[Google Scholar]
  • 65. Callewaert L, Verrijdt G, Haelens A, Claessens FDifferential effect of small ubiquitin-like modifier (SUMO)-ylation of the androgen receptor in the control of cooperativity on selective versus canonical response elements. Mol Endocrinol. 2004;18(6):1438–49.[PubMed][Google Scholar]
  • 66. Cheng J, Bawa T, Lee P, Gong L, Yeh ETRole of desumoylation in the development of prostate cancer. Neoplasia. 2006;8(8):667–76.[Google Scholar]
  • 67. Bawa-Khalfe T, Cheng J, Wang Z, Yeh ETInduction of the SUMO-specific protease 1 transcription by the androgen receptor in prostate cancer cells. J Biol Chem. 2007;282(52):37341–9.[PubMed][Google Scholar]
  • 68. Kaikkonen S, Jaaskelainen T, Karvonen U, Rytinki MM, Makkonen H, Gioeli D, Paschal BM, Palvimo JJSUMO-specific protease 1 (SENP1) reverses the hormone-augmented SUMOylation of androgen receptor and modulates gene responses in prostate cancer cells. Mol Endocrinol. 2009;23(3):292–307.[Google Scholar]
  • 69. Mukherjee S, Thomas M, Dadgar N, Lieberman AP, Iniguez-Lluhi JASmall ubiquitin-like modifier (SUMO) modification of the androgen receptor attenuates polyglutamine-mediated aggregation. J Biol Chem. 2009;284(32):21296–306.[Google Scholar]
  • 70. Lin HK, Wang L, Hu YC, Altuwaijri S, Chang CPhosphorylation-dependent ubiquitylation and degradation of androgen receptor by Akt require Mdm2 E3 ligase. EMBO J. 2002;21(15):4037–48.[Google Scholar]
  • 71. Xu K, Shimelis H, Linn DE, Jiang R, Yang X, Sun F, Guo Z, Chen H, Li W, Kong X, Melamed J, Fang S, Xiao Z, Veenstra TD, Qiu YRegulation of androgen receptor transcriptional activity and specificity by RNF6-induced ubiquitination. Cancer Cell. 2009;15(4):270–82.[Google Scholar]
  • 72. He B, Bai S, Hnat AT, Kalman RI, Minges JT, Patterson C, Wilson EMAn androgen receptor NH2-terminal conserved motif interacts with the COOH terminus of the Hsp70-interacting protein (CHIP) J Biol Chem. 2004;279(29):30643–53.[PubMed][Google Scholar]
  • 73. Morishima Y, Wang AM, Yu Z, Pratt WB, Osawa Y, Lieberman APCHIP deletion reveals functional redundancy of E3 ligases in promoting degradation of both signaling proteins and expanded glutamine proteins. Hum Mol Genet. 2008;17(24):3942–52.[Google Scholar]
  • 74. Wang AM, Morishima Y, Clapp KM, Peng HM, Pratt WB, Gestwicki JE, Osawa Y, Lieberman APInhibition of hsp70 by methylene blue affects signaling protein function and ubiquitination and modulates polyglutamine protein degradation. J Biol Chem. 2010;285(21):15714–23.[Google Scholar]
  • 75. Adachi H, Waza M, Tokui K, Katsuno M, Minamiyama M, Tanaka F, Doyu M, Sobue GCHIP overexpression reduces mutant androgen receptor protein and ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model. J Neurosci. 2007;27(19):5115–26.[Google Scholar]
  • 76. Simental JA, Sar M, Lane MV, French FS, Wilson EMTranscriptional activation and nuclear targeting signals of the human androgen receptor. J Biol Chem. 1991;266(1):510–8.[PubMed][Google Scholar]
  • 77. Jenster G, van der Korput HA, Trapman J, Brinkmann AOIdentification of two transcription activation units in the N-terminal domain of the human androgen receptor. J Biol Chem. 1995;270(13):7341–6.[PubMed][Google Scholar]
  • 78. Chamberlain NL, Whitacre DC, Miesfeld RLDelineation of two distinct type 1 activation functions in the androgen receptor amino-terminal domain. J Biol Chem. 1996;271(43):26772–8.[PubMed][Google Scholar]
  • 79. Reid J, Kelly SM, Watt K, Price NC, McEwan IJ. Conformational analysis of the androgen receptor amino-terminal domain involved in transactivation. Influence of structure-stabilizing solutes and protein-protein interactions. J Biol Chem. 2002;277(22):20079–86.[PubMed]
  • 80. He B, Kemppainen JA, Wilson EMFXXLF and WXXLF sequences mediate the NH2-terminal interaction with the ligand binding domain of the androgen receptor. J Biol Chem. 2000;275(30):22986–94.[PubMed][Google Scholar]
  • 81. Doesburg P, Kuil CW, Berrevoets CA, Steketee K, Faber PW, Mulder E, Brinkmann AO, Trapman JFunctional in vivo interaction between the amino-terminal, transactivation domain and the ligand binding domain of the androgen receptor. Biochemistry. 1997;36(5):1052–64.[PubMed][Google Scholar]
  • 82. Ikonen T, Palvimo JJ, Janne OAInteraction between the amino- and carboxyl-terminal regions of the rat androgen receptor modulates transcriptional activity and is influenced by nuclear receptor coactivators. J Biol Chem. 1997;272(47):29821–8.[PubMed][Google Scholar]
  • 83. Langley E, Kemppainen JA, Wilson EMIntermolecular NH2-/carboxyl-terminal interactions in androgen receptor dimerization revealed by mutations that cause androgen insensitivity. J Biol Chem. 1998;273(1):92–101.[PubMed][Google Scholar]
  • 84. Zhou ZX, Lane MV, Kemppainen JA, French FS, Wilson EMSpecificity of ligand-dependent androgen receptor stabilization: receptor domain interactions influence ligand dissociation and receptor stability. Mol Endocrinol. 1995;9(2):208–18.[PubMed][Google Scholar]
  • 85. Peterziel H, Culig Z, Stober J, Hobisch A, Radmayr C, Bartsch G, Klocker H, Cato ACMutant androgen receptors in prostatic tumors distinguish between aminoacid-sequence requirements for transactivation and ligand binding. Int J Cancer. 1995;63(4):544–50.[PubMed][Google Scholar]
  • 86. Berrevoets CA, Doesburg P, Steketee K, Trapman J, Brinkmann AOFunctional interactions of the AF-2 activation domain core region of the human androgen receptor with the amino-terminal domain and with the transcriptional coactivator TIF2 (transcriptional intermediary factor2) Mol Endocrinol. 1998;12(8):1172–83.[PubMed][Google Scholar]
  • 87. Bevan CL, Hoare S, Claessens F, Heery DM, Parker MGThe AF1 and AF2 domains of the androgen receptor interact with distinct regions of SRC1. Mol Cell Biol. 1999;19(12):8383–92.[Google Scholar]
  • 88. He B, Kemppainen JA, Voegel JJ, Gronemeyer H, Wilson EMActivation function 2 in the human androgen receptor ligand binding domain mediates interdomain communication with the NH(2)-terminal domain. J Biol Chem. 1999;274(52):37219–25.[PubMed][Google Scholar]
  • 89. Nedelsky NB, Pennuto M, Smith RB, Palazzolo I, Moore J, Nie Z, Neale G, Taylor JPNative functions of the androgen receptor are essential to pathogenesis in a Drosophila model of spinobulbar muscular atrophy. Neuron. 2010;67(6):936–52.[Google Scholar]
  • 90. Orr CR, Montie HL, Liu Y, Bolzoni E, Jenkins SC, Wilson EM, Joseph JD, McDonnell DP, Merry DEAn interdomain interaction of the androgen receptor is required for its aggregation and toxicity in spinal and bulbar muscular atrophy. J Biol Chem. 2010;285(46):35567–77.[Google Scholar]
  • 91. Katsuno M, Adachi H, Kume A, Li M, Nakagomi Y, Niwa H, Sang C, Kobayashi Y, Doyu M, Sobue GTestosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Neuron. 2002;35(5):843–54.[PubMed][Google Scholar]
  • 92. Takeyama K, Ito S, Yamamoto A, Tanimoto H, Furutani T, Kanuka H, Miura M, Tabata T, Kato SAndrogen-dependent neurodegeneration by polyglutamine-expanded human androgen receptor in Drosophila. Neuron. 2002;35(5):855–64.[PubMed][Google Scholar]
  • 93. Sopher BL, Thomas PS, Jr, LaFevre-Bernt MA, Holm IE, Wilke SA, Ware CB, Jin LW, Libby RT, Ellerby LM, La Spada ARAndrogen receptor YAC transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF164 in the motor neuron degeneration. Neuron. 2004;41(5):687–99.[PubMed][Google Scholar]
  • 94. Nakajima H, Kimura F, Nakagawa T, Ikemoto T, Furutama D, Shinoda K, Kato S, Shimizu A, Ohsawa NEffects of androgen receptor polyglutamine tract expansion on proliferation of NG108-15 cells. Neurosci Lett. 1997;222(2):83–6.[PubMed][Google Scholar]
  • 95. Becker M, Martin E, Schneikert J, Krug HF, Cato ACCytoplasmic localization and the choice of ligand determine aggregate formation by androgen receptor with amplified polyglutamine stretch. J Cell Biol. 2000;149(2):255–62.[Google Scholar]
  • 96. Darrington RS, Butler R, Leigh PN, McPhaul MJ, Gallo JMLigand-dependent aggregation of polyglutamine-expanded androgen receptor in neuronal cells. Neuroreport. 2002;13(16):2117–20.[PubMed][Google Scholar]
  • 97. Walcott JL, Merry DELigand promotes intranuclear inclusions in a novel cell model of spinal and bulbar muscular atrophy. J Biol Chem. 2002;277(52):50855–9.[PubMed][Google Scholar]
  • 98. Montie HL, Cho MS, Holder L, Liu Y, Tsvetkov AS, Finkbeiner S, Merry DECytoplasmic retention of polyglutamine-expanded androgen receptor ameliorates disease via autophagy in a mouse model of spinal and bulbar muscular atrophy. Hum Mol Genet. 2009;18(11):1937–50.[Google Scholar]
  • 99. McManamny P, Chy HS, Finkelstein DI, Craythorn RG, Crack PJ, Kola I, Cheema SS, Horne MK, Wreford NG, O’Bryan MK, De Kretser DM, Morrison JRA mouse model of spinal and bulbar muscular atrophy. Hum Mol Genet. 2002;11(18):2103–11.[PubMed][Google Scholar]
  • 100. Chevalier-Larsen ES, O’Brien CJ, Wang H, Jenkins SC, Holder L, Lieberman AP, Merry DECastration restores function and neurofilament alterations of aged symptomatic males in a transgenic mouse model of spinal and bulbar muscular atrophy. J Neurosci. 2004;24(20):4778–86.[Google Scholar]
  • 101. Yu Z, Dadgar N, Albertelli M, Gruis K, Jordan C, Robins DM, Lieberman APAndrogen-dependent pathology demonstrates myopathic contribution to the Kennedy disease phenotype in a mouse knock-in model. J Clin Invest. 2006;116(10):2663–72.[Google Scholar]
  • 102. Katsuno M, Adachi H, Doyu M, Minamiyama M, Sang C, Kobayashi Y, Inukai A, Sobue GLeuprorelin rescues polyglutamine-dependent phenotypes in a transgenic mouse model of spinal and bulbar muscular atrophy. Nat Med. 2003;9(6):768–73.[PubMed][Google Scholar]
  • 103. Avila DM, Allman DR, Gallo JM, McPhaul MJAndrogen receptors containing expanded polyglutamine tracts exhibit progressive toxicity when stably expressed in the neuroblastoma cell line, SH-SY 5Y. Exp Biol Med (Maywood) 2003;228(8):982–90.[PubMed][Google Scholar]
  • 104. Brooks BP, Paulson HL, Merry DE, Salazar-Grueso EF, Brinkmann AO, Wilson EM, Fischbeck KHCharacterization of an expanded glutamine repeat androgen receptor in a neuronal cell culture system. Neurobiol Dis. 1997;3(4):313–23.[PubMed][Google Scholar]
  • 105. Bingham PM, Scott MO, Wang S, McPhaul MJ, Wilson EM, Garbern JY, Merry DE, Fischbeck KHStability of an expanded trinucleotide repeat in the androgen receptor gene in transgenic mice. Nat Genet. 1995;9(2):191–6.[PubMed][Google Scholar]
  • 106. Thomas PS, Jr, Fraley GS, Damian V, Woodke LB, Zapata F, Sopher BL, Plymate SR, La Spada ARLoss of endogenous androgen receptor protein accelerates motor neuron degeneration and accentuates androgen insensitivity in a mouse model of X-linked spinal and bulbar muscular atrophy. Hum Mol Genet. 2006;15(14):2225–38.[PubMed][Google Scholar]
  • 107. Yu Z, Dadgar N, Albertelli M, Scheller A, Albin RL, Robins DM, Lieberman APAbnormalities of germ cell maturation and sertoli cell cytoskeleton in androgen receptor 113 CAG knock-in mice reveal toxic effects of the mutant protein. Am J Pathol. 2006;168(1):195–204.[Google Scholar]
  • 108. McCampbell A, Taylor JP, Taye AA, Robitschek J, Li M, Walcott J, Merry D, Chai Y, Paulson H, Sobue G, Fischbeck KHCREB-binding protein sequestration by expanded polyglutamine. Hum Mol Genet. 2000;9(14):2197–202.[PubMed][Google Scholar]
  • 109. Abel A, Walcott J, Woods J, Duda J, Merry DEExpression of expanded repeat androgen receptor produces neurologic disease in transgenic mice. Hum Mol Genet. 2001;10(2):107–16.[PubMed][Google Scholar]
  • 110. Suzuki E, Zhao Y, Ito S, Sawatsubashi S, Murata T, Furutani T, Shirode Y, Yamagata K, Tanabe M, Kimura S, Ueda T, Fujiyama S, Lim J, Matsukawa H, Kouzmenko AP, Aigaki T, Tabata T, Takeyama K, Kato SAberrant E2F activation by polyglutamine expansion of androgen receptor in SBMA neurotoxicity. Proc Natl Acad Sci U S A. 2009;106(10):3818–22.[Google Scholar]
  • 111. Katsuno M, Adachi H, Minamiyama M, Waza M, Doi H, Kondo N, Mizoguchi H, Nitta A, Yamada K, Banno H, Suzuki K, Tanaka F, Sobue GDisrupted transforming growth factor-beta signaling in spinal and bulbar muscular atrophy. J Neurosci. 2010;30(16):5702–12.[Google Scholar]
  • 112. Nucifora FC, Jr, Sasaki M, Peters MF, Huang H, Cooper JK, Yamada M, Takahashi H, Tsuji S, Troncoso J, Dawson VL, Dawson TM, Ross CAInterference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity. Science. 2001;291(5512):2423–8.[PubMed][Google Scholar]
  • 113. Jiang H, Nucifora FC, Jr, Ross CA, DeFranco DBCell death triggered by polyglutamine-expanded huntingtin in a neuronal cell line is associated with degradation of CREB-binding protein. Hum Mol Genet. 2003;12(1):1–12.[PubMed][Google Scholar]
  • 114. Minamiyama M, Katsuno M, Adachi H, Waza M, Sang C, Kobayashi Y, Tanaka F, Doyu M, Inukai A, Sobue GSodium butyrate ameliorates phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Hum Mol Genet. 2004;13(11):1183–92.[PubMed][Google Scholar]
  • 115. Taylor JP, Taye AA, Campbell C, Kazemi-Esfarjani P, Fischbeck KH, Min KTAberrant histone acetylation, altered transcription, and retinal degeneration in a Drosophila model of polyglutamine disease are rescued by CREB-binding protein. Genes Dev. 2003;17(12):1463–8.[Google Scholar]
  • 116. McCampbell A, Taye AA, Whitty L, Penney E, Steffan JS, Fischbeck KHHistone deacetylase inhibitors reduce polyglutamine toxicity. Proc Natl Acad Sci U S A. 2001;98(26):15179–84.[Google Scholar]
  • 117. Ross CA, Poirier MAProtein aggregation and neurodegenerative disease. Nat Med. 2004;10(Suppl):S10–7.[PubMed][Google Scholar]
  • 118. Takahashi T, Katada S, Onodera OPolyglutamine diseases: where does toxicity come from? what is toxicity? where are we going? J Mol Cell Biol. 2010;2(4):180–91.[PubMed][Google Scholar]
  • 119. Li M, Chevalier-Larsen ES, Merry DE, Diamond MISoluble androgen receptor oligomers underlie pathology in a mouse model of spinobulbar muscular atrophy. J Biol Chem. 2007;282(5):3157–64.[PubMed][Google Scholar]
  • 120. Silva-Fernandes A, doCosta CM, Duarte-Silva S, Oliveira P, Botelho CM, Martins L, Mariz JA, Ferreira T, Ribeiro F, Correia-Neves M, Costa C, Maciel PMotor uncoordination and neuropathology in a transgenic mouse model of Machado-Joseph disease lacking intranuclear inclusions and ataxin-3 cleavage products. Neurobiol Dis. 2010;40(1):163–76.[PubMed][Google Scholar]
  • 121. Jochum T, Ritz ME, Schuster C, Funderburk SF, Jehle K, Schmitz K, Brinkmann F, Hirtz M, Moss D, Cato ACToxic and non-toxic aggregates from the SBMA and normal forms of androgen receptor have distinct oligomeric structures. Biochim Biophys Acta. 2012;1822(6):1070–8.[PubMed][Google Scholar]
  • 122. Palazzolo I, Nedelsky NB, Askew CE, Harmison GG, Kasantsev AG, Taylor JP, Fischbeck KH, Pennuto MB2 attenuates polyglutamine-expanded androgen receptor toxicity in cell and fly models of spinal and bulbar muscular atrophy. J Neurosci Res. 2010;88(10):2207–16.[Google Scholar]
  • 123. Taylor JP, Tanaka F, Robitschek J, Sandoval CM, Taye A, Markovic-Plese S, Fischbeck KHAggresomes protect cells by enhancing the degradation of toxic polyglutamine-containing protein. Hum Mol Genet. 2003;12(7):749–57.[PubMed][Google Scholar]
  • 124. Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner SInclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature. 2004;431(7010):805–10.[PubMed][Google Scholar]
  • 125. Cooper JK, Schilling G, Peters MF, Herring WJ, Sharp AH, Kaminsky Z, Masone J, Khan FA, Delanoy M, Borchelt DR, Dawson VL, Dawson TM, Ross CATruncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture. Hum Mol Genet. 1998;7(5):783–90.[PubMed][Google Scholar]
  • 126. Kim YJ, Yi Y, Sapp E, Wang Y, Cuiffo B, Kegel KB, Qin ZH, Aronin N, DiFiglia MCaspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington’s disease brains, associate with membranes, and undergo calpain-dependent proteolysis. Proc Natl Acad Sci U S A. 2001;98(22):12784–9.[Google Scholar]
  • 127. Sun B, Fan W, Balciunas A, Cooper JK, Bitan G, Steavenson S, Denis PE, Young Y, Adler B, Daugherty L, Manoukian R, Elliott G, Shen W, Talvenheimo J, Teplow DB, Haniu M, Haldankar R, Wypych J, Ross CA, Citron M, Richards WGPolyglutamine repeat length-dependent proteolysis of huntingtin. Neurobiol Dis. 2002;11(1):111–22.[PubMed][Google Scholar]
  • 128. Tanaka Y, Igarashi S, Nakamura M, Gafni J, Torcassi C, Schilling G, Crippen D, Wood JD, Sawa A, Jenkins NA, Copeland NG, Borchelt DR, Ross CA, Ellerby LMProgressive phenotype and nuclear accumulation of an amino-terminal cleavage fragment in a transgenic mouse model with inducible expression of full-length mutant huntingtin. Neurobiol Dis. 2006;21(2):381–91.[PubMed][Google Scholar]
  • 129. Ikeda H, Yamaguchi M, Sugai S, Aze Y, Narumiya S, Kakizuka AExpanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo. Nat Genet. 1996;13(2):196–202.[PubMed][Google Scholar]
  • 130. Paulson HL, Perez MK, Trottier Y, Trojanowski JQ, Subramony SH, Das SS, Vig P, Mandel JL, Fischbeck KH, Pittman RNIntranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron. 1997;19(2):333–44.[PubMed][Google Scholar]
  • 131. Klement IA, Skinner PJ, Kaytor MD, Yi H, Hersch SM, Clark HB, Zoghbi HY, Orr HTAtaxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell. 1998;95(1):41–53.[PubMed][Google Scholar]
  • 132. Saudou F, Finkbeiner S, Devys D, Greenberg MEHuntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell. 1998;95(1):55–66.[PubMed][Google Scholar]
  • 133. Peters MF, Nucifora FC, Jr, Kushi J, Seaman HC, Cooper JK, Herring WJ, Dawson VL, Dawson TM, Ross CANuclear targeting of mutant Huntingtin increases toxicity. Mol Cell Neurosci. 1999;14(2):121–8.[PubMed][Google Scholar]
  • 134. Kobayashi Y, Miwa S, Merry DE, Kume A, Mei L, Doyu M, Sobue GCaspase-3 cleaves the expanded androgen receptor protein of spinal and bulbar muscular atrophy in a polyglutamine repeat length-dependent manner. Biochem Biophys Res Commun. 1998;252(1):145–50.[PubMed][Google Scholar]
  • 135. Wellington CL, Ellerby LM, Hackam AS, Margolis RL, Trifiro MA, Singaraja R, McCutcheon K, Salvesen GS, Propp SS, Bromm M, Rowland KJ, Zhang T, Rasper D, Roy S, Thornberry N, Pinsky L, Kakizuka A, Ross CA, Nicholson DW, Bredesen DE, Hayden MRCaspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract. J Biol Chem. 1998;273(15):9158–67.[PubMed][Google Scholar]
  • 136. Young JE, Garden GA, Martinez RA, Tanaka F, Sandoval CM, Smith AC, Sopher BL, Lin A, Fischbeck KH, Ellerby LM, Morrison RS, Taylor JP, La Spada ARPolyglutamine-expanded androgen receptor truncation fragments activate a Bax-dependent apoptotic cascade mediated by DP5/Hrk. J Neurosci. 2009;29(7):1987–97.[Google Scholar]
  • 137. Butler R, Leigh PN, McPhaul MJ, Gallo JMTruncated forms of the androgen receptor are associated with polyglutamine expansion in X-linked spinal and bulbar muscular atrophy. Hum Mol Genet. 1998;7(1):121–7.[PubMed][Google Scholar]
  • 138. Chan HY, Warrick JM, Andriola I, Merry D, Bonini NMGenetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila. Hum Mol Genet. 2002;11(23):2895–904.[PubMed][Google Scholar]
  • 139. Pratt WB, Toft DORegulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery. Exp Biol Med (Maywood) 2003;228(2):111–33.[PubMed][Google Scholar]
  • 140. Georget V, Terouanne B, Nicolas JC, Sultan CMechanism of antiandrogen action: key role of hsp90 in conformational change and transcriptional activity of the androgen receptor. Biochemistry. 2002;41(39):11824–31.[PubMed][Google Scholar]
  • 141. Fang Y, Fliss AE, Robins DM, Caplan AJHsp90 regulates androgen receptor hormone binding affinity in vivo. J Biol Chem. 1996;271(45):28697–702.[PubMed][Google Scholar]
  • 142. Cardozo CP, Michaud C, Ost MC, Fliss AE, Yang E, Patterson C, Hall SJ, Caplan AJC-terminal Hsp-interacting protein slows androgen receptor synthesis and reduces its rate of degradation. Arch Biochem Biophys. 2003;410(1):134–40.[PubMed][Google Scholar]
  • 143. Thomas M, Harrell JM, Morishima Y, Peng HM, Pratt WB, Lieberman APPharmacologic and genetic inhibition of hsp90-dependent trafficking reduces aggregation and promotes degradation of the expanded glutamine androgen receptor without stress protein induction. Hum Mol Genet. 2006;15(11):1876–83.[PubMed][Google Scholar]
  • 144. Stenoien DL, Cummings CJ, Adams HP, Mancini MG, Patel K, DeMartino GN, Marcelli M, Weigel NL, Mancini MAPolyglutamine-expanded androgen receptors form aggregates that sequester heat shock proteins, proteasome components and SRC-1, and are suppressed by the HDJ-2 chaperone. Hum Mol Genet. 1999;8(5):731–41.[PubMed][Google Scholar]
  • 145. Kobayashi Y, Kume A, Li M, Doyu M, Hata M, Ohtsuka K, Sobue GChaperones Hsp70 and Hsp40 suppress aggregate formation and apoptosis in cultured neuronal cells expressing truncated androgen receptor protein with expanded polyglutamine tract. J Biol Chem. 2000;275(12):8772–8.[PubMed][Google Scholar]
  • 146. Adachi H, Katsuno M, Minamiyama M, Sang C, Pagoulatos G, Angelidis C, Kusakabe M, Yoshiki A, Kobayashi Y, Doyu M, Sobue GHeat shock protein 70 chaperone overexpression ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model by reducing nuclear-localized mutant androgen receptor protein. J Neurosci. 2003;23(6):2203–11.[Google Scholar]
  • 147. Katsuno M, Sang C, Adachi H, Minamiyama M, Waza M, Tanaka F, Doyu M, Sobue GPharmacological induction of heat-shock proteins alleviates polyglutamine-mediated motor neuron disease. Proc Natl Acad Sci U S A. 2005;102(46):16801–6.[Google Scholar]
  • 148. Waza M, Adachi H, Katsuno M, Minamiyama M, Sang C, Tanaka F, Inukai A, Doyu M, Sobue G17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration. Nat Med. 2005;11(10):1088–95.[PubMed][Google Scholar]
  • 149. Tokui K, Adachi H, Waza M, Katsuno M, Minamiyama M, Doi H, Tanaka K, Hamazaki J, Murata S, Tanaka F, Sobue G17-DMAG ameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in an SBMA model mouse. Hum Mol Genet. 2009;18(5):898–910.[PubMed][Google Scholar]
  • 150. Yu Z, Wang AM, Robins DM, Lieberman APAltered RNA splicing contributes to skeletal muscle pathology in Kennedy disease knock-in mice. Dis Model Mech. 2009;2(9–10):500–7.[Google Scholar]
  • 151. Ranganathan S, Harmison GG, Meyertholen K, Pennuto M, Burnett BG, Fischbeck KHMitochondrial abnormalities in spinal and bulbar muscular atrophy. Hum Mol Genet. 2009;18(1):27–42.[Google Scholar]
  • 152. Yu Z, Wang AM, Adachi H, Katsuno M, Sobue G, Yue Z, Robins DM, Lieberman APMacroautophagy is regulated by the UPR-mediator CHOP and accentuates the phenotype of SBMA mice. PLoS Genet. 2011;7(10):e1002321.[Google Scholar]
  • 153. Thomas M, Yu Z, Dadgar N, Varambally S, Yu J, Chinnaiyan AM, Lieberman APThe unfolded protein response modulates toxicity of the expanded glutamine androgen receptor. J Biol Chem. 2005;280(22):21264–71.[PubMed][Google Scholar]
  • 154. Katsuno M, Adachi H, Minamiyama M, Waza M, Tokui K, Banno H, Suzuki K, Onoda Y, Tanaka F, Doyu M, Sobue GReversible disruption of dynactin 1-mediated retrograde axonal transport in polyglutamine-induced motor neuron degeneration. J Neurosci. 2006;26(47):12106–17.[Google Scholar]
  • 155. Kemp MQ, Poort JL, Baqri RM, Lieberman AP, Breedlove SM, Miller KE, Jordan CLImpaired motoneuronal retrograde transport in two models of SBMA implicates two sites of androgen action. Hum Mol Genet. 2011;20(22):4475–90.[Google Scholar]
  • 156. Piccioni F, Pinton P, Simeoni S, Pozzi P, Fascio U, Vismara G, Martini L, Rizzuto R, Poletti AAndrogen receptor with elongated polyglutamine tract forms aggregates that alter axonal trafficking and mitochondrial distribution in motor neuronal processes. FASEB J. 2002;16(11):1418–20.[PubMed][Google Scholar]
  • 157. Szebenyi G, Morfini GA, Babcock A, Gould M, Selkoe K, Stenoien DL, Young M, Faber PW, MacDonald ME, McPhaul MJ, Brady STNeuropathogenic forms of huntingtin and androgen receptor inhibit fast axonal transport. Neuron. 2003;40(1):41–52.[PubMed][Google Scholar]
  • 158. Palazzolo I, Stack C, Kong L, Musaro A, Adachi H, Katsuno M, Sobue G, Taylor JP, Sumner CJ, Fischbeck KH, Pennuto MOverexpression of IGF-1 in muscle attenuates disease in a mouse model of spinal and bulbar muscular atrophy. Neuron. 2009;63(3):316–28.[Google Scholar]
  • 159. Jordan CL, Lieberman APSpinal and bulbar muscular atrophy: a motoneuron or muscle disease? Curr Opin Pharmacol. 2008;8(6):752–8.[Google Scholar]
  • 160. Monks DA, Johansen JA, Mo K, Rao P, Eagleson B, Yu Z, Lieberman AP, Breedlove SM, Jordan CLOverexpression of wild-type androgen receptor in muscle recapitulates polyglutamine disease. Proc Natl Acad Sci U S A. 2007;104(46):18259–64.[Google Scholar]
  • 161. Takeshita Y, Fujinaga R, Zhao C, Yanai A, Shinoda KHuntingtin-associated protein 1 (HAP1) interacts with androgen receptor (AR) and suppresses SBMA-mutant-AR-induced apoptosis. Hum Mol Genet. 2006;15(15):2298–312.[PubMed][Google Scholar]
  • 162. Banno H, Katsuno M, Suzuki K, Takeuchi Y, Kawashima M, Suga N, Takamori M, Ito M, Nakamura T, Matsuo K, Yamada S, Oki Y, Adachi H, Minamiyama M, Waza M, Atsuta N, Watanabe H, Fujimoto Y, Nakashima T, Tanaka F, Doyu M, Sobue GPhase 2 trial of leuprorelin in patients with spinal and bulbar muscular atrophy. Ann Neurol. 2009;65(2):140–50.[PubMed][Google Scholar]
  • 163. Katsuno M, Banno H, Suzuki K, Takeuchi Y, Kawashima M, Yabe I, Sasaki H, Aoki M, Morita M, Nakano I, Kanai K, Ito S, Ishikawa K, Mizusawa H, Yamamoto T, Tsuji S, Hasegawa K, Shimohata T, Nishizawa M, Miyajima H, Kanda F, Watanabe Y, Nakashima K, Tsujino A, Yamashita T, Uchino M, Fujimoto Y, Tanaka F, Sobue GEfficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2010;9(9):875–84.[PubMed][Google Scholar]
  • 164. Fernandez-Rhodes LE, Kokkinis AD, White MJ, Watts CA, Auh S, Jeffries NO, Shrader JA, Lehky TJ, Li L, Ryder JE, Levy EW, Solomon BI, Harris-Love MO, La Pean A, Schindler AB, Chen C, Di Prospero NA, Fischbeck KHEfficacy and safety of dutasteride in patients with spinal and bulbar muscular atrophy: a randomised placebo-controlled trial. Lancet Neurol. 2011;10(2):140–7.[Google Scholar]
  • 165. Preisler N, Andersen G, Thogersen F, Crone C, Jeppesen TD, Wibrand F, Vissing JEffect of aerobic training in patients with spinal and bulbar muscular atrophy (Kennedy disease) Neurology. 2009;72(4):317–23.[PubMed][Google Scholar]
  • 166. Dalbello-Haas V, Florence JM, Krivickas LSTherapeutic exercise for people with amyotrophic lateral sclerosis or motor neuron disease. Cochrane Database Syst Rev. 2008;(2):CD005229.[PubMed][Google Scholar]
  • 167. Fryer JD, Yu P, Kang H, Mandel-Brehm C, Carter AN, Crespo-Barreto J, Gao Y, Flora A, Shaw C, Orr HT, Zoghbi HYExercise and genetic rescue of SCA1 via the transcriptional repressor Capicua. Science. 2011;334(6056):690–3.[Google Scholar]
  • 168. D’Abreu A, Franca MC, Jr, Paulson HL, Lopes-Cendes ICaring for Machado-Joseph disease: current understanding and how to help patients. Parkinsonism Relat Disord. 2010;16(1):2–7.[Google Scholar]
  • 169. Yang Z, Chang YJ, Yu IC, Yeh S, Wu CC, Miyamoto H, Merry DE, Sobue G, Chen LM, Chang SS, Chang CASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor. Nat Med. 2007;13(3):348–53.[PubMed][Google Scholar]
  • 170. Pandey UB, Nie Z, Batlevi Y, McCray BA, Ritson GP, Nedelsky NB, Schwartz SL, DiProspero NA, Knight MA, Schuldiner O, Padmanabhan R, Hild M, Berry DL, Garza D, Hubbert CC, Yao TP, Baehrecke EH, Taylor JPHDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature. 2007;447(7146):859–63.[PubMed][Google Scholar]
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.