Hereditary Parkinson's Disease Research Articles

Eukaryotic translation initiation factor EIF4G1 p.Ser637Cys mutation in a family with Parkinson's disease with antecedent essential tremor.

Essential tremor (ET) and Parkinson's disease (PD) are common chronic movement disorders that can cause a substantial degree of disability. However, the etiology underlying these two conditions remains poorly understood. In the present study, Whole-exome sequencing of peripheral blood samples from the proband and Sanger sequencing of the other 18 family members, and pedigree analysis of four generations of 29 individuals with both ET and PD in a nonconsanguineous Chinese family were performed. Specifically, family members who had available medical information, including historical documentation and physical examination records, were included. A novel c.1909A>T (p.Ser637Cys) missense mutation was identified in the eukaryotic translation initiation factor 4γ1 (EIF4G1) gene as the candidate likely responsible for both conditions. In total, 9 family members exhibited tremor of the bilateral upper limbs and/or head starting from ages of ≥40 years, 3 of whom began showing evidence of PD in their 70s. Eukaryotic initiation factor 4 (eIF4)G1, a component of the translation initiation complex eIF4F, serves as a scaffold protein that interacts with many initiation factors and then binds to the 40S ribosomal subunit. The EIF4G1 (p.Ser637Cys) might inhibit the recruitment of the mRNA to the ribosome. In conclusion, the results from the present study suggested that EIF4G1 may be responsible for the hereditary PD with 'antecedent ET' reported in the family assessed.

Pathogenesis of Parkinson's disease: from hints from monogenic familial PD to biomarkers.

Twenty-five years have passed since the causative gene for familial Parkinson's disease (PD), Parkin (now PRKN), was identified in 1998; PRKN is the most common causative gene in young-onset PD. Parkin encodes a ubiquitin-protein ligase, and Parkin is involved in mitophagy, a type of macroautophagy, in concert with PTEN-induced kinase 1 (PINK1). Both gene products are also involved in mitochondrial quality control. Among the many genetic PD-causing genes discovered, discovering PRKN as a cause of juvenile-onset PD has significantly impacted other neurodegenerative disorders. This is because the involvement of proteolytic systems has been suggested as a common mechanism in neurodegenerative diseases in which inclusion body formation is observed. The discovery of the participation of PRKN in PD has brought attention to the involvement of the proteolytic system in neurodegenerative diseases. Our research group has successfully isolated and identified CHCHD2, which is involved in the mitochondrial electron transfer system, and prosaposin (PSAP), which is involved in the lysosomal system, in this Parkin mechanism. Hereditary PD is undoubtedly an essential clue to solitary PD, and at least 25 or so genes and loci have been reported so far. This number of genes indicates that PD is a very diverse group of diseases. Currently, the diagnosis of PD is based on clinical symptoms and imaging studies. Although highly accurate diagnostic criteria have been published, early diagnosis is becoming increasingly important in treatment strategies for neurodegenerative diseases. Here, we also describe biomarkers that our group is working on.

Comprehensive analysis of clinical and biological features in Parkinson's disease associated with the LRRK2 G2019S mutation: Data from the PPMI study.

The Parkinson's Progression Marker Initiative (PPMI) aims to identify biomarkers for Parkinson's disease (PD) risk, onset, and progression. This study focuses on the G2019S missense mutation in the LRRK2 gene, which is associated with hereditary and sporadic PD. Utilizing data from the PPMI database, we conducted an analysis of baseline clinical characteristics, as well as serum and cerebrospinal fluid levels in two groups: patients with PD with the G2019S mutation (PD + G2019S) and patients with PD without the mutation (PD-G2019S). Multiple linear regression and longitudinal analysis were performed, controlling for confounding factors. Compared to the PD-G2019S group, the PD + G2019S group showed more obvious initial motor dysfunction-higher baseline Movement Disorder Society-Sponsored Revision of the Unified Parkinson Disease Rating Scale (MDS-UPDRS) scores (false discovery rate [FDR]-adjusted p < 0.001), but progressed more slowly. Mechanism of Coordinated Access and activities of daily living (ADL) scores were lower at baseline (FDR-adjusted p < 0.001), whereas Scales for Outcomes of Parkinson's Disease (SCOPA)-Thermoregulatory (FDR-adjusted p = 0.015) scores were higher, emphasizing the increase of non-motor symptoms associated with LRRK2-G2019S mutation. During the follow-up period, the motor and non-motor symptoms changed dynamically with time, and there were longitudinal differences in the scores of MDS-UPDRS (FDR-adjusted PI = 0.013, PII = 0.008, PIV < 0.001), Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (FDR-adjusted p = 0.027), SCOPA-Thermoregulatory (FDR-adjusted p = 0.021), and ADL (FDR-adjusted p = 0.027) scale scores. PD associated with the LRRK2 G2019S mutation demonstrated more severe symptoms at baseline but slower progression. Motor complications and thermoregulatory disorders were more pronounced.

Frequency of Hereditary and GBA1-Related Parkinsonism in Latin America: A Systematic Review and Meta-Analysis.

Identifying hereditary parkinsonism is valuable for diagnosis, genetic counseling, patient prioritization in trials, and studying the disease for personalized therapies. However, most studies were conducted in Europeans, and limited data exist on admixed populations like those from Latin America. This study aims to assess the frequency and distribution of genetic parkinsonism in Latin America. We conducted a systematic review and meta-analysis of the frequency of parkinsonian syndromes associated with genetic pathogenic variants in Latin America. We defined hereditary parkinsonism as those caused by the genes outlined by the MDS Nomenclature of Genetic Movement Disorders and heterozygous carriers of GBA1 pathogenic variants. A systematic search was conducted in PubMed, Web of Science, Embase, and LILACS in August 2022. Researchers reviewed titles and abstracts, and disagreements were resolved by a third researcher. After this screening, five researchers reanalyzed the selection criteria and extracted information based on the full paper. The frequency for each parkinsonism-related gene was determined by the presence of pathogenic/likely pathogenic variants among screened patients. Cochran's Q and I2 tests were used to quantify heterogeneity. Meta-regression, publication bias tests, and sensitivity analysis regarding study quality were also used for LRRK2-, PRKN-, and GBA1-related papers. We included 73 studies involving 3014 screened studies from 16 countries. Among 7668 Latin American patients, pathogenic variants were found in 19 different genes. The frequency of the pathogenic variants in LRRK2 was 1.38% (95% confidence interval [CI]: 0.52-2.57), PRKN was 1.16% (95% CI: 0.08-3.05), and GBA1 was 4.17% (95% CI: 2.57-6.08). For all meta-analysis, heterogeneity was high and publication bias tests were negative, except for PRKN, which was contradictory. Information on the number of pathogenic variants in the other genes is further presented in the text. This study provides insights into hereditary and GBA1-related parkinsonism in Latin America. Lower GBA1 frequencies compared to European/North American cohorts may result from limited access to gene sequencing. Further research is vital for regional prevalence understanding, enabling personalized care and therapies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Differences in EEG Event-Related Potentials during Dual Task in Parkinson's Disease Carriers and Non-Carriers of the G2019S-LRRK2 Mutation.

The G2019S-LRRK2 gene mutation is a common cause of hereditary Parkinson's disease (PD), associated with a higher frequency of the postural instability gait difficulty (PIGD) motor phenotype yet with preserved cognition. This study investigated neurophysiological changes during motor and cognitive tasks in PD patients with and without the G2019S-LRRK2 mutation. 33 iPD patients and 22 LRRK2-PD patients performed the visual Go/NoGo task (VGNG) during sitting (single-task) and walking (dual-task) while wearing a 64-channel EEG cap. Event-related potentials (ERP) from Fz and Pz, specifically N200 and P300, were extracted and analyzed to quantify brain activity patterns. The LRRK2-PD group performed better in the VGNG than the iPD group (group*task; p = 0.05). During Go, the iPD group showed reduced N2 amplitude and prolonged N2 latency during walking, whereas the LRRK2-PD group showed only shorter latency (group*task p = 0.027). During NoGo, opposite patterns emerged; the iPD group showed reduced N2 and increased P3 amplitudes during walking while the LRRK2-PD group demonstrated increased N2 and reduced P3 (N2: group*task, p = 0.010, P3: group*task, p = 0.012). The LRRK2-PD group showed efficient early cognitive processes, reflected by N2, resulting in greater neural synchronization and prominent ERPs. These processes are possibly the underlying mechanisms for the observed better cognitive performance as compared to the iPD group. As such, future applications of intelligent medical sensing should be capable of capturing these electrophysiological patterns in order to enhance motor-cognitive functions.

Interlinked role of ASN, TDP-43 and Miro1 with parkinopathy: Focus on targeted approach against neuropathy in parkinsonism.

Parkinsonism is a complex neurodegenerative disease that is difficult to differentiate because of its idiopathic and unknown origins. The hereditary parkinsonism known as autosomal recessive-juvenile parkinsonism (AR-JP) is marked by tremors, dyskinesias, dystonic characteristics, and manifestations that improve sleep but do not include dementia. This was caused by deletions and point mutations in PARK2 (chromosome 6q25.2-27). Diminished or unusual sensations (paresthesias), loss of neuron strength both in the CNS and peripheral nerves, and lack of motor coordination are the hallmarks of neuropathy in parkinsonism. The incidence of parkinsonism during oxidative stress and ageing is associated with parkinopathy. Parkinopathy is hypothesized to be triggered by mutation of the parkin (PRKN) gene and loss of normal physiological functions of PRKN proteins, which triggers their pathogenic aggregation due to conformational changes. Two important genes that control mitochondrial health are PRKN and phosphatase and tensin homologue deleted on chromosome 10-induced putative kinase 1 (PINK1). Overexpression of TAR DNA-binding protein-43 (TDP-43) increases the aggregation of insoluble PRKN proteins in OMM. Foreign α-synuclein (ASN)promotes parkinopathy via S-nitrosylation and hence has a neurotoxic effect on dopaminergic nerves. Miro1(Miro GTPase1), a member of the RAS superfamily, is expressed in nerve cells. Due to PINK1/PRKN and Miro1's functional relationship, an excess of mitochondrial calcium culminates in the destruction of dopaminergic neurons. An interlinked understanding of TDP-43, PINK1/PRKN, ASN, and Miro1 signalling in the communication among astrocytes, microglia, neurons, and immune cells within the brain explored the pathway of neuronal death and shed light on novel strategies for the diagnosis and treatment of parkinsonism.

LRRK2 deficiency protects the heart against myocardial infarction injury in mice via the P53/HMGB1 pathway.

LRRK2 is a Ser/Thr kinase with multiple functional domains. Studies have shown that LRRK2 mutations are closely related to hereditary Parkinson's disease. However, its role in cardiovascular disease, especially in myocardial infarction, is unclear. The aim of this study was to explore the functional role of LRRK2 in myocardial infarction. Wild-type and LRRK2-knockout mice were subjected to coronary artery ligation (left anterior descending) to establish a myocardial infarction model. Neonatal rat cardiomyocytes were subjected to hypoxia to induce hypoxic injury in vitro. We found increased LRRK2 expression levels in the infarct periphery in mouse hearts and hypoxic cardiomyocytes. LRRK2-deficient mice exhibited decreased death rates and reduced infarction areas compared to wild-type controls 14 days after infarction. LRRK2-deficient mice showed reduced left ventricular fibrosis and inflammatory responses, as well as improved cardiac function. In the in vitro study, LRRK2 silencing decreased cleaved caspase-3 activity, reduced cardiomyocyte apoptosis, and diminished hypoxia-induced inflammation. However, LRRK2 overexpression enhanced cleaved caspase-3 activity, increased the number of apoptotic cardiomyocytes, and caused remarkable hypoxia-induced inflammation. When examining the underlying mechanisms, we found that hypoxia increased HIFα expression, which enhanced LRRK2 expression. LRRK2 induced high expression of HMGB1 via P53. When HMGB1 was blocked using an anti-HMGB1 antibody, the deleterious effects caused by LRRK2 overexpression following hypoxia were inhibited in cardiomyocytes. In summary, LRRK2 deficiency protects the heart against myocardial infarction injury. The mechanism underlying this effect involves the P53-HMGB1 pathway.

Cognitive deficits and altered cholinergic innervation in young adult male mice carrying a Parkinson's disease Lrrk2G2019S knockin mutation

Impaired executive function is a common and debilitating non-motor symptom of idiopathic and hereditary Parkinson's disease (PD), but there is little understanding of the underlying pathophysiological mechanisms and circuits. The G2019S mutation in the kinase domain of leucine-rich repeat kinase 2 (LRRK2) greatly increases risk for late-onset PD, and non-manifesting LRRK2G2019S carriers can also exhibit early and significant cognitive impairment. Here, we subjected young adult male mice carrying a Lrrk2G2019S knockin mutation to touchscreen-based operant tasks that measure attention, goal-directed learning and cognitive flexibility, all of which rely on frontal-striatal connectivity and are strongly modulated by cholinergic innervation. In a visuospatial attention task, mutant mice exhibited significantly more omissions and longer response latencies than controls that could not be attributed to deficits in motivation, visual sensory perception per se or locomotion, thereby suggesting impairments in divided attention and/or action-selection as well as generally slower information processing speed. Pretreating mice with the acetylcholinesterase inhibitor donepezil normalized both higher omission rates and longer response latencies in the mutants, but did not affect any performance metric in controls. Strikingly, cholinergic fiber density in cortical areas PL/IL and DMS (dorsomedial striatum) was significantly sparser in mutants than in controls, while further behavioral interrogation of the mutants revealed significant impairments in action-outcome associations but preserved cognitive flexibility. These data suggest that the Lrrk2G2019S mutation negatively impacts cholinergic innervation anatomically and functionally by young adulthood, impairing corticostriatal network function in ways that may contribute to early PD-associated executive function deficits.

A protein mutated in Parkinson's disease prevents damage of metabolites and proteins caused by a glycolytic metabolite

The accumulation of cellular damage is suspected to contribute to aging and neurodegenerative diseases. Oxidative stress and environmental factors likely play a role, but other damaging agents likely remain to be discoveredHere we report that an enzyme mutated in hereditary Parkinson’s disease achieves the seemingly impossible task to prevent damage caused by a glycolytic metabolite without affecting the metabolite itself. Inactivation of this enzyme in model systems ranging from flies to human cells leads to the accumulation of a wide range of metabolites and proteins damaged by a newly discovered covalent modification.Thus, this enzyme represents a highly conserved strategy to prevent damage in cells that perform glycolysis. Thereby, it interrupts a fundamental link between carbohydrate metabolism and a type of cellular damage that might contribute to the development of Parkinson’s disease.

Interleukin-6 triggers toxic neuronal iron sequestration in response to pathological α-synuclein.

SUMMARYα-synuclein (α-syn) aggregation and accumulation drive neurodegeneration in Parkinson’s disease (PD). The substantia nigra of patients with PD contains excess iron, yet the underlying mechanism accounting for this iron accumulation is unclear. Here, we show that misfolded α-syn activates microglia, which release interleukin 6 (IL-6). IL-6, via its trans-signaling pathway, induces changes in the neuronal iron transcriptome that promote ferrous iron uptake and decrease cellular iron export via a pathway we term the cellular iron sequestration response, or CISR. The brains of patients with PD exhibit molecular signatures of the IL-6-mediated CISR. Genetic deletion of IL-6, or treatment with the iron chelator deferiprone, reduces pathological α-syn toxicity in a mouse model of sporadic PD. These data suggest that IL-6-induced CISR leads to toxic neuronal iron accumulation, contributing to synuclein-induced neurodegeneration.

Isogenic models of Parkinson’s disease as a tool for studying the effect of mutation G2019S in LRRK2 gene on calcium signaling

Disturbance of calcium signaling is widely observed in various neurodegenerative pathologies including Parkinson's disease (PD). The G2019S mutation in the LRRK2 gene is one of the most common causes of hereditary PD. However, molecular mechanisms of pathological changes remain poorly understood. Recently, intriguing data has been obtained on the effect of the G2019S mutation on the calcium dynamics in the patient-specific dopaminergic neurons. Here we have been studied the effect of this mutation on store-operated calcium entry (SOCE) in isogenic dopaminergic neurons.

Parkinson's disease protein PARK7 prevents metabolite and protein damage caused by a glycolytic metabolite

Cells are continuously exposed to potentially dangerous compounds. Progressive accumulation of damage is suspected to contribute to neurodegenerative diseases and aging, but the molecular identity of the damage remains largely unknown. Here we report that PARK7, an enzyme mutated in hereditary Parkinson's disease, prevents damage of proteins and metabolites caused by a metabolite of glycolysis. We found that the glycolytic metabolite 1,3-bisphosphoglycerate (1,3-BPG) spontaneously forms a novel reactive intermediate that avidly reacts with amino groups. PARK7 acts by destroying this intermediate, thereby preventing the formation of proteins and metabolites with glycerate and phosphoglycerate modifications on amino groups. As a consequence, inactivation of PARK7 (or its orthologs) in human cell lines, mouse brain, and Drosophila melanogaster leads to the accumulation of these damaged compounds, most of which have not been described before. Our work demonstrates that PARK7 function represents a highly conserved strategy to prevent damage in cells that metabolize carbohydrates. This represents a fundamental link between metabolism and a type of cellular damage that might contribute to the development of Parkinson's disease.

The Protein-Protein Interaction Network of Hereditary Parkinsonism Genes Is a Hierarchical Scale-Free Network.

PurposeHereditary parkinsonism genes consist of causative genes of familial Parkinson’s disease (PD) with a locus symbol prefix (PARK genes) and hereditary atypical parkinsonian disorders that present atypical features and limited responsiveness to levodopa (non-PARK genes). Although studies have shown that hereditary parkinsonism genes are related to idiopathic PD at the phenotypic, gene expression, and genomic levels, no study has systematically investigated connectivity among the proteins encoded by these genes at the protein-protein interaction (PPI) level.Materials and MethodsTopological measurements and physical interaction enrichment were performed to assess PPI networks constructed using some or all the proteins encoded by hereditary parkinsonism genes (n=96), which were curated using the Online Mendelian Inheritance in Man database and literature.ResultsNon-PARK and PARK genes were involved in common functional modules related to autophagy, mitochondrial or lysosomal organization, catecholamine metabolic process, chemical synapse transmission, response to oxidative stress, neuronal apoptosis, regulation of cellular protein catabolic process, and vesicle-mediated transport in synapse. The hereditary parkinsonism proteins formed a single large network comprising 51 nodes, 83 edges, and three PPI pairs. The probability of degree distribution followed a power-law scaling behavior, with a degree exponent of 1.24 and a correlation coefficient of 0.92. LRRK2 was identified as a hub gene with the highest degree of betweenness centrality; its physical interaction enrichment score was 1.28, which was highly significant.ConclusionBoth PARK and non-PARK genes show high connectivity at the PPI and biological functional levels.

Targeting of Lysosomal Pathway Genes for Parkinson's Disease Modification: Insights From Cellular and Animal Models.

Previous genetic studies on hereditary Parkinson's disease (PD) have identified a set of pathogenic gene mutations that have strong impacts on the pathogenicity of PD. In addition, genome-wide association studies (GWAS) targeted to sporadic PD have nominated an increasing number of genetic variants that influence PD susceptibility. Although the clinical and pathological characteristics in hereditary PD are not identical to those in sporadic PD, α-synuclein, and LRRK2 are definitely associated with both types of PD, with LRRK2 mutations being the most frequent cause of autosomal-dominant PD. On the other hand, a significant portion of risk genes identified from GWAS have been associated with lysosomal functions, pointing to a critical role of lysosomes in PD pathogenesis. Experimental studies have suggested that the maintenance or upregulation of lysosomal activity may protect against neuronal dysfunction or degeneration. Here we focus on the roles of representative PD gene products that are implicated in lysosomal pathway, namely LRRK2, VPS35, ATP13A2, and glucocerebrosidase, and provide an overview of their disease-associated functions as well as their cooperative actions in the pathogenesis of PD, based on the evidence from cellular and animal models. We also discuss future perspectives of targeting lysosomal activation as a possible strategy to treat neurodegeneration.

The burden of rare damaging variants in hereditary atypical parkinsonism genes is increased in patients with Parkinson’s disease

Increased burdens of rare coding variants in genes related to lysosomal storage disease or mitochondrial pathways were reported to be associated with idiopathic Parkinson’s disease. Under a hypothesis that the burden of damaging rare coding variants is increased in causative genes for hereditary parkinsonism, we analyzed the burdens of rare coding variants with a case-control design. Two cohorts of whole-exome sequencing data and a cohort of genome-wide genotyping data of clinically validated idiopathic Parkinson’s disease cases and controls, which were open to the public, were used. The sequence kernel association test–optimal was used to analyze the burden of rare variants in the hereditary parkinsonism gene set, which was constructed from the Online Mendelian Inheritance in Man database through manual curation. The hereditary parkinsonism gene set consisted of 17 genes with a locus symbol prefix for familial Parkinson’s disease and 75 hereditary atypical parkinsonism genes. We detected a significant association of enriched burdens of predicted damaging rare coding variants in hereditary parkinsonism genes in all three datasets. Meta-analyses of the rare variant burden test in a subgroup of gene sets revealed an association between burdens of rare damaging variants with PD in a hereditary atypical parkinsonism gene set, but not in a subgroup gene set with a locus symbol prefix for familial Parkinson’s disease. Our results highlight the roles of rare damaging variants in causative genes for hereditary atypical parkinsonian disorders. We propose that Mendelian genes associated with hereditary disorders accompanying parkinsonism are involved in Parkinson’s disease-related genetic networks.

Different cortical excitability profiles in hereditary brain iron and copper accumulation.

Neurodegeneration with brain iron accumulation (NBIA) and Wilson's disease (WD) is considered the prototype of neurodegenerative disorders characterised by the overloading of iron and copper in the central nervous system. Growing evidence has unveiled the involvement of these metals in brain cortical neurotransmission. Aim of this study was to assess cortical excitability profile due to copper and iron overload. Three patients affected by NBIA, namely two patients with a recessive hereditary parkinsonism (PARK9) and one patient with aceruloplasminemia and 7 patients with neurological WD underwent transcranial magnetic stimulation (TMS) protocols to assess cortical excitability. Specifically, we evaluated the motor thresholds that reflect membrane excitability related to the voltage-gated sodium channels in the neurons of the motor system and the ease of activation of motor cortex via glutamatergic networks, and ad hoc TMS protocols to probe inhibitory-GABAergic (short interval intracortical inhibition, SICI; short-latency afferent inhibition, SAI; cortical silent period, CSP) and excitatory intracortical circuitry (intracortical facilitation, ICF). Patients with NBIA exhibited an abnormal prolongation of CSP respect to HC and WD patients. On the contrary, neurological WD displayed higher motor thresholds and reduced CSP and SICI. Hereditary conditions due to overload of copper and iron exhibited peculiar cortical excitability profiles that can help during differential diagnosis between these conditions. Moreover, such results can give us more clues about the role of metals in acquired neurodegenerative disorders, such as Parkinson disease, Alzheimer disease, and multiple sclerosis.

The G2019S variant of leucine-rich repeat kinase 2 (LRRK2) alters endolysosomal trafficking by impairing the function of the GTPase RAB8A

Mutations in the gene encoding for leucine-rich repeat kinase 2 (LRRK2) are a common cause of hereditary Parkinson's disease. LRRK2 regulates various intracellular vesicular trafficking pathways, including endolysosomal degradative events such as epidermal growth factor receptor (EGFR) degradation. Recent studies have revealed that a subset of RAB proteins involved in secretory and endocytic recycling are LRRK2 kinase substrates in vivo. However, the effects of LRRK2-mediated phosphorylation of these substrates on membrane trafficking remain unknown. Here, using an array of immunofluorescence and pulldown assays, we report that expression of active or phosphodeficient RAB8A variants rescues the G2019S LRRK2–mediated effects on endolysosomal membrane trafficking. Similarly, up-regulation of the RAB11–Rabin8–RAB8A cascade, which activates RAB8A, also reverted these trafficking deficits. Loss of RAB8A mimicked the effects of G2019S LRRK2 on endolysosomal trafficking and decreased RAB7A activity. Expression of pathogenic G2019S LRRK2 or loss of RAB8A interfered with EGFR degradation by causing its accumulation in a RAB4-positive endocytic compartment, which was accompanied by a deficit in EGFR recycling and was rescued upon expression of active RAB7A. Dominant-negative RAB7A expression resulted in similar deficits in EGF degradation, accumulation in a RAB4 compartment, and deficits in EGFR recycling, which were all rescued upon expression of active RAB8A. Taken together, these findings suggest that, by impairing RAB8A function, pathogenic G2019S LRRK2 deregulates endolysosomal transport and endocytic recycling events.

Pipeline to gene discovery - Analysing familial Parkinsonism in the Queensland Parkinson's Project

IntroductionFamily based study designs provide an informative resource to identify disease-causing mutations. The Queensland Parkinson's Project (QPP) has been involved in numerous genetic screening studies; however, details of the families enrolled into the register have not been comprehensively reported. This article characterises the families enrolled in the QPP and summarises monogenic forms of hereditary Parkinsonism found in the register. MethodThe presence of pathogenic point mutations and copy number variations (CNVs) were, generally, screened in a sample of over 1000 PD patients from the total of 1725. Whole exome sequencing (WES) was performed on eighteen probands from multiplex families. ResultsThe QPP contains seventeen incidences of confirmed monogenic forms of PD, including LRRK2 p.G2019S, VPS35 p.D620N, SNCA duplications and PARK2 p.G430D (hom) & exon 4 deletion (hom). Of these seventeen, five belong to multi-incident families, while another eight have a family history of at least one other case of PD. In additional families, WES did not identify known forms of monogenic Parkinsonism; however, three heterozygous mutations in PARK2, p.R275W, p.Q34fs, and a 40bp deletion in exon 3 were identified. Of these three mutations, only the 40bp deletion segregated with disease in a dominant inheritance pattern. ConclusionEighteen probands have screened negative for known CNVs and mutations that cause clear monogenic forms of PD. Each family is a candidate for further genetic analysis to identify genetic variants segregating with disease. The families enrolled in the QPP provide a useful resource to aid in identifying novel forms of monogenic PD.

Control of RAB7 activity and localization through the retromer-TBC1D5 complex enables RAB7-dependent mitophagy.

Retromer is an endosomal multi‐protein complex that organizes the endocytic recycling of a vast range of integral membrane proteins. Here, we establish an additional retromer function in controlling the activity and localization of the late endosomal small GTPase RAB7. Surprisingly, we found that RAB7 not only decorates late endosomes or lysosomes, but is also present on the endoplasmic reticulum, trans‐Golgi network, and mitochondrial membranes, a localization that is maintained by retromer and the retromer‐associated RAB7‐specific GAP TBC1D5. In the absence of either TBC1D5 or retromer, RAB7 activity state and localization are no longer controlled and hyperactivated RAB7 expands over the entire lysosomal domain. This lysosomal accumulation of hyperactivated RAB7 results in a striking loss of RAB7 mobility and overall depletion of the inactive RAB7 pool on endomembranes. Functionally, we establish that this control of RAB7 activity is not required for the recycling of retromer‐dependent cargoes, but instead enables the correct sorting of the autophagy related transmembrane protein ATG9a and autophagosome formation around damaged mitochondria during Parkin‐mediated mitophagy.

Characterization of a presymptomatic stage in a Drosophila Parkinson's disease model: Unveiling dopaminergic compensatory mechanisms

Parkinson's disease (PD) is a degenerative disorder characterized by several motor symptoms including shaking, rigidity, slow movement and difficult walking, which has been associated to the death of nigro-striatal dopaminergic neurons. >90% of PD patients also present olfactory dysfunction. Although the molecular mechanisms responsible for this disease are not clear, hereditary PD is linked to mutations in specific genes, including the PTEN-induced putative kinase 1 (PINK1).In this work we provide for the first time a thorough temporal description of the behavioral effects induced by a mutation in the PINK1 gene in adult Drosophila, a previously described animal model for PD. Our data suggests that the motor deficits associated to PD are fully revealed only by the third week of age. However, olfactory dysfunction is detected as early as the first week of age. We also provide immunofluorescence and neurochemical data that let us propose for the first time the idea that compensatory changes occur in this Drosophila model for PD. These compensatory changes are associated to specific components of the dopaminergic system: the biosynthetic enzymes, Tyrosine hydroxylase and Dopa decarboxylase, and the Dopamine transporter, a plasma membrane protein involved in maintaining dopamine extracellular levels at physiologically relevant levels.Thus, our behavioral, immunofluorescence and neurochemical data help define for the first time presymptomatic and symptomatic phases in this PD animal model, and that compensatory changes occur in the dopaminergic neurons in the presymptomatic stage.