One of the greatest advances in Parkinson's disease (PD) research in the past two decades has been a better understanding of PD genetics. Of the many candidate genes investigated, the best studied include LRRK2, SNCA, VPS35, Parkin, PINK1, and DJ1. The authors review the key clinical features of these monogenic forms, as well as for the prevalent risk factor gene, GBA, including the phenotype, clinical course, and treatment response. They also outline areas for future investigation: longitudinal studies of PD's clinical course, the identification of its premotor manifestations, and its specific mechanisms of pathogenicity.

An understanding of the genetic etiology of Parkinson disease (PD) has become imperative for the modern-day neurologist. Although genetic forms cause only a minority of PD, the disease mechanisms they elucidate advance the understanding of idiopathic cases. Moreover, recently identified susceptibility variants contribute to complex-etiology PD and broaden the contribution of genetics beyond familial and early-onset cases. Dominantly inherited monogenic forms mimic idiopathic PD and are caused by mutations or copy number variations of SNCA, LRRK2, and VPS35. On the other hand, early-onset forms are associated with PARKIN, PINK1, and DJ1 mutations, nominating mitochondrial dysfunction and oxidative stress as another important molecular pathway in the causation of the disease, in addition to alpha-synuclein accumulation. Common variants in GBA are consistently identified by association studies and may be considered to be a major risk gene for PD, with markedly reduced penetrance. Other genes have been proposed to be associated with PD; however, these only cause very rare forms, if at all. Current guidelines recommend testing for LRRK2 variants in familial PD or in specific populations (ancestry), and for the recessive genes in early-onset PD. However, gene panels have made testing for multiple forms of genetic PD a viable approach.

Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in newborn premature infants. Clinical studies show increased incidence of NEC in premature infants with enteral formula feeding; however, pathogenesis remains unclear. To identify the NEC-related proteins for molecular mechanisms, we applied proteomics analysis to characterize changes in the protein expression profile of newborn premature piglet intestines with NEC developed after enteral formula feeding for 24 h. Changes in protein expression were identified using 2-dimensional gel electrophoresis and peptide mass fingerprinting with MS as well as western blotting analysis. Nineteen differentially expressed proteins were identified and these have roles in oxidative stress, chaperone, signal transduction, protein folding and degradation, oxygen transport, signal transduction, and energy metabolism. Proteins with increased levels include manganese-containing superoxide dismutase and hemoglobin subunit and proteins with decreased expression include sorbitol dehydrogenase, mitochondrial aldehyde dehydrogenase 2, glucose-regulated protein 75, CRY protein, snail homolog 3, thyroid hormone-binding protein precursor, and DJ1 (Parkinson's disease 7) etc. The data provided novel mechanistic insights into the pathogenesis of NEC and the insults of a formulated diet to the premature gut.

Excess nitric oxide (NO) induces apoptosis in some cell types, including macrophages. Heat shock protein of 70 kDa (hsp70) has been reported to protect cells from various stresses, including apoptosis-inducing stimuli. Several mammalian cytosolic DnaJ homologs, partner chaperones of hsp70 family members, have been identified. We asked if a DnaJ homolog is required to prevent NO-mediated apoptosis. When mouse macrophage-like RAW 264.7 cells were treated with an NO donor, SNAP, apoptosis occurred. This apoptosis could be prevented by pretreatment of the cells with heat or a low dose of SNAP. Under these conditions, levels of hsc70 (an hsp70 member) remained unchanged, whereas hsp70 was markedly induced. Of the DnaJ homologs dj1 (hsp40/hdj-1) was strongly induced and dj2 (HSDJ/hdj-2) was moderately induced. In transfection experiments, hsp70, hsc70, dj1 or dj2 alone was ineffective in preventing NO-mediated apoptosis. In contrast, both dj1 and dj2, in combination with hsc70 or hsp70, prevented the cells from apoptosis. The hsp70-DnaJ chaperone pairs exerted their anti-apoptotic effects upstream of caspase 3 activation, and apparently upstream of cytochrome c release from mitochondria.

Dissecting the genetics of Alzheimer's disease (AD) and Parkinson's disease (PD) has contributed significantly to our understanding of the pathogenesis of neurodegeneration in these two complex disorders. For AD, three highly penetrant genes (amyloid precursor protein (APP, PSEN1 and PSEN2) and one susceptibility gene (APOE) have been identified. For PD, seven genes (SNCA, Parkin, UCHL1, NR4A2, DJ1, PINK1 and LRRK2) have been found. These genes explain only a small proportion of AD and PD patients and are mostly associated with an early onset presentation of the disease. APOE remains the only common gene, which increases the risk of both rare early and late onset AD. The ongoing challenge is to unravel the genetics of the most frequent forms of these complex disorders. In the present paper, we briefly review the state of the art in the genetics of AD and PD. We also discuss the prospects of finding new genes associated with common forms of these diseases in light of two hypotheses concerning the genetic variation of complex diseases: common disease/common variants and common disease/rare variants.

In the previous report (Sonia Angeline et al., 2012), we showed an altered expression of protective proteins in rotenone-induced Parkinson's disease (PD)-like rat model. This model exhibited a marked attenuation in the expression of parkin, C terminus Hsp70 interacting protein (CHIP) and PARK 7 protein (DJ1) while enhanced levels of caspases and ubiquitin were seen. Herein, we confirmed the neuroprotective role of sesamol and naringenin individually on rotenone-induced rodent model of PD. Rotenone administration was given for 11days to generate the PD model (Sonia Angeline et al., 2012). From 11th day onward individual doses of sesamol (15mg/kg) and naringenin (10mg/kg) drugs were given orally to the rotenone PD rat model for 10 consecutive days. The impact of drugs markedly improved the motor skills, body weight, expression of parkin, DJ1, tyrosine hydroxylase and CHIP compared to the group treated with rotenone alone in the striatum and substantia nigra. These results were correlated with the reduction in caspase and ubiquitin levels by immunostaining and immunoblotting. Moreover, improved morphology and survivability of neurons were seen upon sesamol and naringenin treatment in the same rat PD model. Further we confirmed the efficacy of neuroprotective biomolecule administration on muscle from the above PD model and observed the restoration in muscle morphology, elevated level of parkin, DJ1, differential expression of heat shock proteins and reduced cell death. To conclude, for the first time we are demonstrating the comprehensive role of sesamol and naringenin (rotenone-induced PD model) in neuro and myoprotection that would have great clinical significance.

Our knowledge regarding the genetics of Parkinson's disease (PD) and parkinsonism has evolved dramatically during the past decade, with the discovery of numerous loci and genes. The LRRK2 gene has emerged as the most commonly involved in both familial and sporadic PD. Several variants in LRRK2 and SNCA have been associated with an increased risk of sporadic PD. PRKN, PINK1 and DJ1 mutations cause early-onset recessively inherited PD. Autosomal dominant dementia and parkinsonism is caused by mutations in the MAPT gene, and in the most recently discovered PGRN gene.

Parkinson's disease (PD) is a common neurodegenerative disease and typically presents with tremor, rigidity, bradykinesia, and postural instability. The hallmark pathological features of PD are loss of dopaminergic neurons in the substantia nigra (SN) and the presence of neuronal intracellular Lewy body (LB) inclusions. In general, PD is sporadic; however, familial PD, while uncommon, can be inherited in an autosomal dominant (AD) or autosomal recessive (AR) manner. The molecular investigations of proteins encoded by PD-linked genes have clarified that ADPD is associated with α-synuclein and LRRK2, while ARPD is linked to Parkin, PINK1, DJ1, and ATP13A2. Understanding these genes can bring insights into this disease and create possible genetic tests for early diagnosis. Long-term pharmacological treatment is so far disappointing, probably due to unwanted complications and decreasing drug efficacy. Several strategies have been proposed and tested as alternatives for PD. Cellular transplantation of dopamine-secreting stem cells opens the door to new therapeutic avenues for restoration of the functions of degenerative and/or damaged neurons in PD.

Parkinson's disease (PD) is a common neurodegenerative disorder of adulthood characterized clinically by rigidity, bradykinesia, resting tremor, and postural instability. The annual incidence of PD ranges between 16 and 19 individuals per 100,000 (Twelves et al., Mov Disord 2003;18:19-31). Historically, PD has been commonly viewed as an idiopathic or environmentally triggered condition. However, as is true with most common conditions, there have been several families reported with PD who demonstrate a classic Mendelian pattern of inheritance. To date, nine genetic loci have been reported and four pathogenic genes have been identified: alpha-synuclein, parkin, DJ1, and PINK1. Families with alterations in these genes or linked sites demonstrate either recessive or dominant inheritance patterns and may have typical and/or atypical symptoms, with an age of onset extending from the second to the sixth decade. Commercial tests for parkin and alpha-synuclein mutations are now available. We predict that physicians, particularly neurologists, increasingly will be approached for information and referrals regarding genetic testing. To assist patients and their families, physicians will not only need to know when such testing is likely to yield a meaningful result but also be aware of the possible social and emotional consequences of testing. The following is a review of what is currently known about the genetics of PD within this context. We discuss what is known about genetic testing for Huntington's disease, a well-described model for genetic testing in a neurodegenerative disorder. We explore the utility, appropriateness, and possible implications of genetic testing for diagnostic and presymptomatic purposes.

Mutations in the DJ-1 gene have been shown to cause a rare autosomal-recessive genetic form of Parkinson's disease (PD). The function of DJ-1 and its role in PD development has been linked to multiple pathways, however its exact role in the development of PD has remained elusive. It is thought that DJ-1 may play a role in regulating reactive oxygen species (ROS) formation and overall oxidative stress in cells through directly scavenging ROS itself, or through the regulation of ROS scavenging systems such as glutathione (GSH) or thioredoxin (Trx) or ROS producing complexes such as complex I of the electron transport chain. Previous work in this laboratory has demonstrated that isolated brain mitochondria consume H2O2 predominantly by the Trx/Thioredoxin Reductase (TrxR)/Peroxiredoxin (Prx) system in a respiration dependent manner (Drechsel et al., Journal of Biological Chemistry, 2010). Therefore we wanted to determine if mitochondrial H2O2 consumption was altered in brains from DJ-1 deficient mice (DJ-1(-/-)). Surprisingly, DJ-1(-/-) mice showed an increase in mitochondrial respiration-dependent H2O2 consumption compared to controls. To determine the basis of the increased H2O2 consumption in DJ1(-/-) mice, the activities of Trx, Thioredoxin Reductase (TrxR), GSH, glutathione disulfide (GSSG) and glutathione reductase (GR) were measured. Compared to control mice, brains from DJ-1(-/-) mice showed an increase in (1) mitochondrial Trx activity, (2) GSH and GSSG levels and (3) mitochondrial glutaredoxin (GRX) activity. Brains from DJ-1(-/-) mice showed a decrease in mitochondrial GR activity compared to controls. The increase in the enzymatic activities of mitochondrial Trx and total GSH levels may account for the increased H2O2 consumption observed in the brain mitochondria in DJ-1(-/-) mice perhaps as an adaptive response to chronic DJ-1 deficiency.

Although researchers are pursuing "disease modifying" medications to slow or stop Parkinson's disease (PD) progression, a myriad of agents with protective properties in cell cultures and animal models have yielded few treatments in clinical practice. Developing safe and effective treatments with disease-modifying/neuroprotective mechanisms of action and identifying patients in the pre-motor phase will be a challenge. The implication of tyrosine hydroxylase (TH), the enzyme that catalyzes the formation of L-3,4-dihydroxyphenylalanine, in the pathogenesis of PD at different levels makes it a promising candidate for developing efficient treatment based on correcting or bypassing the enzyme deficiency. TH is also the key enzyme for immunorreactivity in PD models and is used to assess the efficacy of novel disease-modifying medications. PD animal models are genetic: alpha-synuclein models, parkin (PINK 1 and DJ1) and leucine-rich repeat kinase 2 or pharmacological and neurotoxic: reserpine, 6-hydroxydopamine, 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine, rotenone, paraquat/maneb, and trichloroethylene. This review is focused on the state of art of PD models, the relationship with TH, and potential neuroprotective agents to treat PD. The latter include gene therapy, transplantation, erythropoietin, natural phenolic compounds, doxycycline, ethyl pyruvate, 9-methyl-beta-carboline, vascular endothelial growth factor, simvastatin, zonisamide, modafinil, melatonin, cannabinoids, rottlerin, fluoxetine, paroxetine, coenzyme Q10, N-acetylcysteine and vaccines like Bacille Calmette-Guerin, with different proposed mechanisms of action. Also of note is the link between hypovitaminosis D and neurodegeneration opening new perspectives in research with TH genes and PD models treated with vitamin D. Translational scientists can contribute to a better understanding of the pathogenesis of PD and lead to more effective treatments.

BACKGROUND

The underlying pathways that drive retinal neurogenesis and synaptogenesis are still relatively poorly understood. Protein expression analysis can provide direct insight into these complex developmental processes. The aim of this study was therefore to employ proteomic analysis to study the developing chick retina throughout embryonic (E) development commencing at day 12 through 13, 17, 19 and post-hatch (P) 1 and 33 days.

RESULTS

2D proteomic and mass spectrometric analysis detected an average of 1514 spots per gel with 15 spots demonstrating either modulation or constitutive expression identified via MS. Proteins identified included alpha and beta-tubulin, alpha enolase, B-creatine kinase, gamma-actin, platelet-activating factor (PAF), PREDICTED: similar to TGF-beta interacting protein 1, capping protein (actin filament muscle Z line), nucleophosmin 1 (NPM1), dimethylarginine dimethylaminohydrolase, triosphoaphate isomerase, DJ1, stathmin, fatty acid binding protein 7 (FABP7/B-FABP), beta-synuclein and enhancer of rudimentary homologue.

CONCLUSIONS

This study builds upon previous proteomic investigations of retinal development and represents the addition of a unique data set to those previously reported. Based on reported bioactivity some of the identified proteins are most likely to be important to normal retinal development in the chick. Continued analysis of the dynamic protein populations present at the early stages and throughout retinal development will increase our understanding of the molecular events underpinning retinogenesis.

DnaJ homologs are cochaperones of the heat shock protein 70 (hsp70) family. Homologs dj1 (hsp40/hdj-1/ DjB1), dj2 (HSDJ/hdj-2/rdj-1/DjA1), and dj3 (cpr3/DNAJ3/HIRIP4/rdj2/DjA2) have been identified in the mammalian cytosol and characterized. In this paper we characterized newly found dj4 (DjA4) and compared it with other chaperones. The dj4 messenger ribonucleic acid (mRNA) and protein were expressed strongly in heart and testis, moderately in brain and ovary, and weakly in other tissues in mice. Dj4 constituted about 1% of the total protein in heart. Testis gave extraspecies of dj4 mRNA and protein in addition to those seen in other tissues. On subcellular fractionation of the mouse heart, dj4 was recovered mostly in the cytosol fraction. In immunocytochemical analysis of the H9c2 heart muscle cells, dj4 and heat shock cognate 70 (hsc70) colocalized in the cytoplasm under normal conditions, whereas they colocalized in the nucleus after heat shock. When H9c2 cells were differentiated by culturing for up to 28 days with a lowered serum concentration, dj4 was increased markedly, dj3 was increased moderately, and dj1 and dj2 were little changed. The homolog dj4 as well as hsp70, dj1, and dj2 were induced in H9c2 cells by heat treatment at 43 degrees C for 30 minutes, whereas hsc70 and dj3 were not induced. Heat pretreatment promoted survival of cells after severe heat shock at 47 degrees C for 90 minutes or 120 minutes. H9c2 cells overexpressing hsp70 were more resistant to severe heat shock, and a better survival was obtained when dj4 or dj2 was co-overexpressed with hsp70. Taking a high concentration of dj4 in heart into consideration, these results suggest that the hsc70/hsp70-dj4 chaperone pair protects the heart muscle cells from various stresses.

A novel homozygous missense mutation (c.773G>> A, p.Arg258Gln) in Synaptojanin 1 (SYNJ1, 21q22.2) has recently been reported in two Italian and one Iranian consanguineous families with autosomal recessive juvenile Parkinsonism (ARJP). Contribution of this synaptic gene related to Parkinsonism phenotypes in other populations still remains unidentified.

An ARJP family with two affected siblings characterized by frequent tremor with bradykinesia and rigidity was recruited in this study. Both siblings showed intense dyskinesia and dystonia on administration of Syndopa. The family was analyzed for both mutations and exon dosage variations in PARKIN, PINK1 and DJ1. Further, whole exome sequencing was performed in two affected and one unaffected sibling in the family.

We identified a novel homozygous mutation (c.1376C>> G, p.Arg459Pro) in SYNJ1 segregating in this family. This p.Arg459Pro mutation was not observed in 285 additional Parkinson disease (PD) samples (32 familial, 81 early onset and 172 late onset) screened by PCR-Sanger-sequencing. It was also absent in dbSNP, 1000 Genomes, ExAC, NHLBI-ESP database and in >250 ethnically matched exomes available in our laboratory. The arginine residue is highly conserved across species and predicted to be damaging by several in silico tools. As with the previous mutation p.Arg258Gln, p.Arg459Pro is also present in Sac 1 domain of SYNJ1 wherein p.Arg258Gln mutation has already been described to impair the phosphatase activity.

We report another novel mutation in SYNJ1 of an Indian consanguineous ARJP family. Finding an additional mutation in this gene further supports the involvement of SYNJ1 in PD pathogenesis across different ethnicities.

Parkinson disease (PD) is the most common neurodegenerative movement disorder and is characterized pathologically by the formation of ubiquitin and SNCA/α-synuclein-containing inclusions (Lewy bodies), dystrophic midbrain dopaminergic (DAergic) terminals, and degeneration of midbrain DAergic neurons. The vast majority of PD occurs sporadically, while approximately 5% of all PD cases are inherited. Genetic mutations of a few genes have been identified as causes of familiar PD, i.e., mutations in SNCA, PARK2/parkin, UCHL1, PARK7/DJ1, PINK1 and LRRK2, leading to DAergic cell death, but variable pathological changes. The evidence supports the hypothesis that several pathogenic mechanisms are likely involved at initial stages of the disease, and eventually they merge to cause parkinsonism. The current challenge facing PD research is to unravel the components in these pathways that contribute to the pathogenesis of PD. Accumulating evidence has implicated dysfunctional autophagy, a regulated lysosomal pathway with a capacity for clearing protein aggregates and cellular organelles, as one of the pathogenic systems contributing to the development of idiopathic PD.

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) were found to be a significant cause of late-onset autosomal dominant forms of Parkinson's disease (PD). To determine the motor characteristics of LRRK2-related disease, we conducted a longitudinal study of 58 G2019S LRRK2-associated PD patients and compared them with genetically undefined (GU) PD patients. Fifty-eight patients diagnosed with PD-related LRRK2 G2019S mutation were included in the study and compared with 54 sporadic PD patients with negative tests for LRRK2 G2019S, PINK1, SNCA, PRKN, and DJ1 mutations. Patients were assessed at baseline and after a follow-up period of 6 years. The Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the Hoehn and Yahr, and the Schwab and England scores were determined. Logistic regression was used to examine associations of G2019S mutation status with motor phenotype and rate of motor decline. The LRRK2-associated PD patients had a mean age of onset of 56.25 ± 12.05 years and in most cases (58.6%) a postural instability gait difficulty (PIGD) phenotype. The mean annual decline in the MDS-UDRS III motor score and the Hoehn and Yahr staging was of 1.3% and 2%, respectively. The PIGD phenotype predicted a more rapid progression of motor impairment. The PD motor phenotype and motor scores were similar in the LRRK2-associated PD group and in the GU PD group, with no significant differences in the progression rate of motor impairment. Motor phenotype seems to be similar in LRRK2-related PD and idiopathic PD.

The protein methyltransferase SETD6 is a key regulator of proliferation and inflammatory processes. However, the role of SETD6 in the regulation of additional cell signaling pathways has not been well studied. Here we show that SETD6 is a negative regulator of the oxidative stress response. Depletion of SETD6 from cells results in elevated Nrf2 levels and a significant increase in Nrf2 antioxidant target gene expression. Using proteomic tools, we uncovered a novel interaction between SETD6 and the oxidative stress sensor DJ1, a protein required for Nrf2-dependent transcription of antioxidant target genes. We show that SETD6 binds DJ1 both in-vitro and in cells but does not methylate DJ1. Under basal conditions, SETD6 and DJ1 are associated at chromatin. Through this interaction, SETD6 inhibits DJ1 activity, which in turn leads to the repression of Nrf2-dependent transcription. In response to oxidative stress, the transcription of Nrf2 antioxidant genes increases. We here show that under this condition, SETD6 mRNA and protein levels are reduced, leading to elevation in Nrf2 expression level and to a weaken interaction between SETD6 and DJ1 at chromatin. Taken together, these findings demonstrate that SETD6 negatively regulates the Nrf2-mediated oxidative stress response through a physical and catalytically independent interaction with DJ1 at chromatin.

Parkinson's disease (PD) is one of the major causes of parkinsonism syndrome. Its characteristic motor symptoms are attributable to dopaminergic neurons loss in the midbrain. Genetic advances have highlighted underlying molecular mechanisms and provided clues to potential therapies. However, most of the studies focusing on the genetic component of PD have been performed on American, European and Asian populations, whereas Arab populations (excluding North African Arabs), particularly Saudis remain to be explored. Here we investigated the genetic causes of PD in Saudis by recruiting 98 PD-cases (sporadic and familial) and screening them for potential pathogenic mutations in PD-established genes; SNCA, PARKIN, PINK1, PARK7/DJ1, LRRK2 and other PD-associated genes using direct sequencing. To our surprise, the screening revealed only three pathogenic point mutations; two in PINK1 and one in PARKIN. In addition to mutational analysis, CNV and cDNA analysis was performed on a subset of patients. Exon/intron dosage alterations in PARKIN were detected and confirmed in 2 cases. Our study suggests that mutations in the ORF of the screened genes are not a common cause of PD in Saudi population; however, these findings by no means exclude the possibility that other genetic events such as gene expression/dosage alteration may be more common nor does it eliminate the possibility of the involvement of novel genes.

Reactive α-dicarbonyls (α-DCs), like methylglyoxal (MGO), accumulate with age and have been implicated in aging and various age-associated pathologies, such as diabetic complications and neurodegenerative disorders like Alzheimer's and Parkinson's diseases. Evolutionarily conserved glyoxalases are responsible for α-DC detoxification; however, their core biochemical regulation has remained unclear. We have established a Caenorhabditis elegans model, based on an impaired glyoxalase (glod-4/GLO1), to broadly study α-DC-related stress. We show that, in comparison to wild-type (N2, Bristol), glod-4 animals rapidly exhibit several pathogenic phenotypes, including hyperesthesia, neuronal damage, reduced motility, and early mortality. We further demonstrate TRPA-1/TRPA1 as a sensor for α-DCs, conserved between worms and mammals. Moreover, TRPA-1 activates SKN-1/Nrf via calcium-modulated kinase signaling, ultimately regulating the glutathione-dependent (GLO1) and co-factor-independent (DJ1) glyoxalases to detoxify α-DCs. Interestingly, this pathway is in stark contrast to the TRPA-1 activation and the ensuing calcium flux implicated in cold sensation in C. elegans, whereby DAF-16/FOXO gets activated via complementary kinase signaling. Finally, a phenotypic drug screen using C. elegans identified podocarpic acid as a novel activator of TRPA1 that rescues α-DC-induced pathologies in C. elegans and mammalian cells. Our work thus identifies TRPA1 as a bona fide drug target for the amelioration of α-DC stress, which represents a viable option to address aging-related pathologies in diabetes and neurodegenerative diseases.

Juvenile parkinsonism is arbitrarily defined as parkinsonian symptoms and signs presenting prior to 21 years of age. Levodopa-responsive juvenile parkinsonism that is consistent with diagnostic criteria for Parkinson's disease is most often caused by mutations in the PARK-Parkin, PARK-PINK1, or PARK-DJ1 genes. However, many other genetic and acquired parkinsonian disorders presenting in childhood or young adulthood are being reported, often with atypical features, such as presence of other movement disorders, cognitive decline, and psychiatric symptoms. The genetic landscape of juvenile parkinsonism is rapidly changing with the discovery of new genes. Although the mainstay of treatment remains levodopa, other symptomatic therapies such as botulinum toxin for focal dystonia, supportive medical therapies, and deep brain stimulation in select cases, may also be used to provide the most optimal long-term outcomes. Since the topic has not been reviewed recently, we aim to provide an update on genetics, differential diagnosis, evaluation, and treatment of juvenile parkinsonism.

Mutations in known genes for inherited forms of Parkinson's disease (PD) account for <30% of familial PD (FPD) implying that more causal gene(s) remain to be identified. We attempted to discover the putative causal variant in an Indian family with autosomal-recessive juvenile Parkinsonism (ARJP), tested negative for mutations in PARK2, PINK1 and DJ1.

Whole exomes of two affected siblings were sequenced. Variants prioritised were screened for segregation with disease in the family by targeted sequencing. Gene thus identified was screened for index/additional exonic mutations, if any, in an independent PD cohort by PCR sequencing. Variants observed were functionally validated in differentiated PC12 cells.

A novel homozygous frameshift mutation, c.89_90insGTCGCCCC in exon 1 of podocalyxin-like gene (PODXL, 7q32-33), resulting in loss of protein, segregated with disease in the family. Mutant allele was absent in 186 healthy controls screened by PCR sequencing and in control exomes available in the laboratory and public databases. Screening of additional 212 sporadic and 68 FPD cases identified three novel heterozygous missense variants namely c.1285C>A, c.1118G>A and c.881G>A in three unrelated cases. Significant differences in neurite branching and length (p<0.0001) were observed in PC12 cells with wild-type and mutant constructs.

Based on the genetic and functional evidence in this study and literature support on the role of PODXL in neural development, a novel frameshift mutation in PODXL seems to be the likely cause of ARJP in this family. This is the first report suggesting the possible role of a neurodevelopmental pathway in PD aetiology.

PARK7 (DJ1) is a multifunctional oxidative stress response protein that protects cells against reactive oxygen species (ROS) and mitochondrial damage. PARK7 defects are known to cause various physiological dysfunctions, including infertility. Asthenozoospermia (AS), i.e. low-motile spermatozoa in the ejaculate, is a common cause of human male infertility. In this study, we found that downregulation of PARK7 resulted in increased levels of lipid peroxide and ROS, decreased mitochondrial membrane potential, and reduced mitochondrial complex I enzyme activity in the spermatozoa from AS patients. Furthermore, it was observed that PARK7 was translocated into the mitochondria of damaged spermatozoa in AS. Finally, we examined the oxidative state of PARK7 and the results demonstrated the enhancement of oxidation, expressed by increased sulfonic acid residues, the highest form of oxidation, as the sperm motility decreased. Taken together, these results revealed that PARK7 deficiency may increase the oxidative stress damage to spermatozoa. Our present findings open new avenues of therapeutic intervention targeting PARK7 for the treatment of AS.

Although Parkinson's disease was long considered a nongenetic disorder, it is now clear that there are multiple predisposing genes, and that the disorder can exhibit either Mendelian or non-Mendelian modes of inheritance. The identification of several of these genes has provided important insights into the pathogenesis of this common complex disorder. This article presents an overview of the genes associated with autosomal recessive Parkinson's disease, including Parkin (PARK2), PINK1 (PARK6), DJ1 (PARK7) and ATP13A2 (PARK9). Recently, it was recognized that mutations in the gene encoding glucocerebrosidase, the enzyme deficient in Gaucher disease, are associated with an increased incidence of parkinsonism. While Gaucher disease is an autosomal recessive inherited disorder, patients with Parkinson's disease can be Gaucher heterozygotes or homozygotes. Elucidating the basis for this association may shed light on new disease mechanisms that contribute to the development of parkinsonism.

Mutant oncogene DJ1 L166P has been linked to a familial form of early-onset Parkinson's disease (PD). The DJ1 mutant deformed C-terminal helices and prevented the formation of a functional DJ1 dimer. Intriguingly, chaperon modulator, BCL2-associated athanogene (BAG1), has been shown to repair DJ1 mutant and restore its functions. Molecular simulation techniques were employed to elucidate protein-protein interactions between BAG1 and DJ1. Interaction of BAG1 with DJ1 showed recovery of disrupted alpha helix structures and H-bonds stabilizing the functional site Cys106. The His126-Pro184 H-bond (hydrogen-bond) critical to maintaining dimer interfaces was also restored and led to the restoration of dimer formation. High conformational to functional DJ1 dimer was confirmed root mean square deviation = 0.74 Å). Results of this suggest several molecular insights on BAG1-DJ1 repair mechanism and may have an impact on advancing PD treatments.