Are lysosomes potential therapeutic targets for Parkinson’s disease?

2021 ◽  
Vol 20 ◽  
Author(s):  
A. Petese ◽  
V. Cesaroni ◽  
S. Cerri ◽  
F. Blandini
Keyword(s):  
Neurodegenerative Disorder ◽  
Association Studies ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Genome Wide Association Studies ◽  
Lysosomal Dysfunction ◽  
Genome Wide ◽  
Nigrostriatal Neurons ◽  
Disease Modifying Treatment ◽  
Alpha Synuclein Aggregation

Background: Parkinson´s disease (PD) is the second most common neurodegenerative disorder, affecting 2-3% of the population over 65 years old. In addition to progressive degeneration of nigrostriatal neurons, the histopathological feature of PD is the accumulation of misfolded α-synuclein protein in abnormal cytoplasmatic inclusions, known as Lewy bodies (LBs). Recently, genome-wide association studies (GWAS) have indicated a clear association of variants within several lysosomal genes with risk for PD. Newly evolving data have been shedding light on the relationship between lysosomal dysfunction and alpha-synuclein aggregation. Defects in lysosomal enzymes could lead to the insufficient clearance of neurotoxic protein materials, possibly leading to selective degeneration of dopaminergic neurons. Specific modulation of lysosomal pathways and their components could be considered a novel opportunity for therapeutic intervention for PD. Aim: The purpose of this review is to illustrate lysosomal biology and describe the role of lysosomal dysfunction in PD pathogenesis. Finally, the most promising novel therapeutic approaches designed to modulate lysosomal activity, as a potential disease-modifying treatment for PD will be highlighted.

scholarly journals Parkinson disease age of onset GWAS: defining heritability, genetic loci and a-synuclein mechanisms

2018 ◽  
Author(s):  
Cornelis Blauwendraat ◽  
Karl Heilbron ◽  
Costanza L. Vallerga ◽  
Sara Bandres-Ciga ◽  
Rainer von Coelln ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Association Studies ◽  
Disease Onset ◽  
Alpha Synuclein ◽  
Genome Wide Association Studies ◽  
Genetic Determinants ◽  
Protein Coding ◽  
Genome Wide ◽  
Alpha Synuclein Aggregation ◽  
Shed Light

AbstractIncreasing evidence supports an extensive and complex genetic contribution to Parkinson’s disease (PD). Previous genome-wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age of onset are largely unknown. Here we performed an age of onset GWAS based on 28,568 PD cases. We estimated that the heritability of PD age of onset due to common genetic variation was ~0.11, lower than the overall heritability of risk for PD (~0.27) likely in part because of the subjective nature of this measure. We found two genome-wide significant association signals, one at SNCA and the other a protein-coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni corrected significant effect at other known PD risk loci, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. In addition, we identified that GBA coding variant carriers had an earlier age of onset compared to non-carriers. Notably, SNCA, TMEM175, SCARB2, BAG3 and GBA have all been shown to either directly influence alpha-synuclein aggregation or are implicated in alpha-synuclein aggregation pathways. Remarkably, other well-established PD risk loci such as GCH1, MAPT and RAB7L1/NUCKS1 (PARK16) did not show a significant effect on age of onset of PD. While for some loci, this may be a measure of power, this is clearly not the case for the MAPT locus; thus genetic variability at this locus influences whether but not when an individual develops disease. We believe this is an important mechanistic and therapeutic distinction. Furthermore, these data support a model in which alpha-synuclein and lysosomal mechanisms impact not only PD risk but also age of disease onset and highlights that therapies that target alpha-synuclein aggregation are more likely to be disease-modifying than therapies targeting other pathways.

scholarly journals TMEM175 deficiency impairs lysosomal and mitochondrial function and increases α-synuclein aggregation

2017 ◽  
Vol 114 (9) ◽  
pp. 2389-2394 ◽  
Author(s):  
Sarah Jinn ◽  
Robert E. Drolet ◽  
Paige E. Cramer ◽  
Andus Hon-Kit Wong ◽  
Dawn M. Toolan ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Neurodegenerative Disorder ◽  
Transmembrane Protein ◽  
Association Studies ◽  
Critical Role ◽  
Lewy Bodies ◽  
Neuronal Model ◽  
Genome Wide Association Studies ◽  
Potential Candidate ◽  
Major Genome

Parkinson disease (PD) is a neurodegenerative disorder pathologically characterized by nigrostriatal dopamine neuron loss and the postmortem presence of Lewy bodies, depositions of insoluble α-synuclein, and other proteins that likely contribute to cellular toxicity and death during the disease. Genetic and biochemical studies have implicated impaired lysosomal and mitochondrial function in the pathogenesis of PD. Transmembrane protein 175 (TMEM175), the lysosomal K+ channel, is centered under a major genome-wide association studies peak for PD, making it a potential candidate risk factor for the disease. To address the possibility that variation in TMEM175 could play a role in PD pathogenesis, TMEM175 function was investigated in a neuronal model system. Studies confirmed that TMEM175 deficiency results in unstable lysosomal pH, which led to decreased lysosomal catalytic activity, decreased glucocerebrosidase activity, impaired autophagosome clearance by the lysosome, and decreased mitochondrial respiration. Moreover, TMEM175 deficiency in rat primary neurons resulted in increased susceptibility to exogenous α-synuclein fibrils. Following α-synuclein fibril treatment, neurons deficient in TMEM175 were found to have increased phosphorylated and detergent-insoluble α-synuclein deposits. Taken together, data from these studies suggest that TMEM175 plays a direct and critical role in lysosomal and mitochondrial function and PD pathogenesis and highlight this ion channel as a potential therapeutic target for treating PD.

scholarly journals Investigation of Autosomal Genetic Sex Differences in Parkinson’s disease

2021 ◽  
Author(s):  
Cornelis Blauwendraat ◽  
Hirotaka Iwaki ◽  
Mary B. Makarious ◽  
Sara Bandres-Ciga ◽  
Hampton Leonard ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Risk ◽  
Neurodegenerative Disorder ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Disease Etiology ◽  
Male And Female ◽  
Y Chromosomes ◽  
Genome Wide

AbstractParkinson’s disease (PD) is a complex neurodegenerative disorder. Males are on average ∼1.5 times more likely to develop PD compared to females. Over the years genome-wide association studies (GWAS) have identified numerous genetic risk factors for PD, however it is unclear whether genetics contribute to disease etiology in a sex-specific manner.In an effort to study sex-specific genetic factors associated with PD, we explored two large genetic datasets from the International Parkinson’s Disease Genomics Consortium and the UK Biobank consisting of 13,020 male PD cases, 7,936 paternal proxy cases, 89,660 male controls, 7,947 female PD cases, 5,473 maternal proxy cases and 90,662 female controls. We performed GWAS meta-analyses to identify distinct patterns of genetic risk contributing to disease in male versus female PD cases.In total 19 genome-wide significant regions were identified, and no sex-specific effects were observed. A high genetic correlation between the male and female PD GWASes was identified (rg=0.877) and heritability estimates were identical between male and female PD cases (∼20%).We did not detect any significant genetic differences between male or female PD cases. Our study does not support the notion that common genetic variation on the autosomes could explain the difference in prevalence of PD between males and females at least when considering the current sample size under study. Further studies are warranted to investigate the genetic architecture of PD explained by X and Y chromosomes and further evaluate environmental effects that could potentially contribute to PD etiology in male versus females.

scholarly journals Polygenic Risk Scores Contribute to Personalized Medicine of Parkinson’s Disease

2021 ◽  
Vol 11 (10) ◽  
pp. 1030
Author(s):  
Mohammad Dehestani ◽  
Hui Liu ◽  
Thomas Gasser
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Association Studies ◽  
Cumulative Effect ◽  
Therapeutic Interventions ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
Genome Wide

Parkinson’s disease (PD) is the second most common neurodegenerative disorder characterized by the loss of dopaminergic neurons. The vast majority of PD patients develop the disease sporadically and it is assumed that the cause lies in polygenic and environmental components. The overall polygenic risk is the result of a large number of common low-risk variants discovered by large genome-wide association studies (GWAS). Polygenic risk scores (PRS), generated by compiling genome-wide significant variants, are a useful prognostic tool that quantifies the cumulative effect of genetic risk in a patient and in this way helps to identify high-risk patients. Although there are limitations to the construction and application of PRS, such as considerations of limited genetic underpinning of diseases explained by SNPs and generalizability of PRS to other populations, this personalized risk prediction could make a promising contribution to stratified medicine and tailored therapeutic interventions in the future.

scholarly journals A histone acetylome-wide association study of Alzheimer’s disease: neuropathology-associated regulatory variation in the human entorhinal cortex

2017 ◽  
Author(s):  
Sarah J. Marzi ◽  
Teodora Ribarska ◽  
Adam R. Smith ◽  
Eilis Hannon ◽  
Jeremie Poschmann ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Entorhinal Cortex ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Association Studies ◽  
Amyloid Β ◽  
Genomic Variation ◽  
Genome Wide Association Studies ◽  
Genome Wide

AbstractAlzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by the progressive accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles in the neocortex. Recent studies have implicated a role for regulatory genomic variation in AD progression, finding widespread evidence for altered DNA methylation associated with neuropathology. To date, however, no study has systematically examined other types of regulatory genomic modifications in AD. In this study, we quantified genome-wide patterns of lysine H3K27 acetylation (H3K27ac) - a robust mark of active enhancers and promoters that is strongly correlated with gene expression and transcription factor binding - in entorhinal cortex samples from AD cases and matched controls (n = 47) using chromatin immunoprecipitation followed by highly parallel sequencing (ChIP-seq). Across ~182,000 robustly detected H3K27ac peak regions, we found widespread acetylomic variation associated with AD neuropathology, identifying 4,162 differential peaks (FDR < 0.05) between AD cases and controls. These differentially acetylated peaks are enriched in disease-specific biological pathways and include regions annotated to multiple genes directly involved in the progression of Aβ and tau pathology (e.g. APP, PSEN1, PSEN2, MAPT), as well as genomic regions containing variants associated with sporadic late-onset AD. This is the first study of variable H3K27ac yet undertaken in AD and the largest study investigating this modification in the entorhinal cortex. In addition to identifying molecular pathways associated with AD neuropathology, we present a framework for genome-wide studies of histone modifications in complex disease, integrating our data with results obtained from genome-wide association studies as well as other epigenetic marks profiled on the same samples.

scholarly journals Gene expression profiles complement the analysis of genomic modifiers of the clinical onset of Huntington disease

2020 ◽  
Vol 29 (16) ◽  
pp. 2788-2802
Author(s):  
Galen E B Wright ◽  
Nicholas S Caron ◽  
Bernard Ng ◽  
Lorenzo Casal ◽  
William Casazza ◽  
...  
Keyword(s):  
Gene Expression ◽  
Huntington Disease ◽  
Neurodegenerative Disorder ◽  
Expression Profiles ◽  
Association Studies ◽  
Modifier Genes ◽  
Cag Repeat ◽  
Supporting Evidence ◽  
Genome Wide Association Studies ◽  
Genome Wide

Abstract Huntington disease (HD) is a neurodegenerative disorder that is caused by a CAG repeat expansion in HTT. The length of this repeat, however, only explains a proportion of the variability in age of onset in patients. Genome-wide association studies have identified modifiers that contribute toward a proportion of the observed variance. By incorporating tissue-specific transcriptomic information with these results, additional modifiers can be identified. We performed a transcriptome-wide association study assessing heritable differences in genetically determined expression in diverse tissues, with genome-wide data from over 4000 patients. Functional validation of prioritized genes was undertaken in isogenic HD stem cells and patient brains. Enrichment analyses were performed with biologically relevant gene sets to identify the core pathways. HD-associated gene coexpression modules were assessed for associations with neurological phenotypes in an independent cohort and to guide drug repurposing analyses. Transcriptomic analyses identified genes that were associated with age of HD onset and displayed colocalization with gene expression signals in brain tissue (FAN1, GPR161, PMS2, SUMF2), with supporting evidence from functional experiments. This included genes involved in DNA repair, as well as novel-candidate modifier genes that have been associated with other neurological conditions. Further, cortical coexpression modules were also associated with cognitive decline and HD-related traits in a longitudinal cohort. In summary, the combination of population-scale gene expression information with HD patient genomic data identified novel modifier genes for the disorder. Further, these analyses expanded the pathways potentially involved in modifying HD onset and prioritized candidate therapeutics for future study.

scholarly journals An Overview of Genome-Wide Association Studies in Multiple Sclerosis

2021 ◽  
pp. 49-65
Author(s):  
Khloud Mubarak Algothmi
Keyword(s):  
Multiple Sclerosis ◽  
Genetic Factors ◽  
Neurodegenerative Disorder ◽  
Association Studies ◽  
Treatment Strategies ◽  
Human Leukocyte ◽  
Genome Wide Association ◽  
Published Data ◽  
Genome Wide Association Studies ◽  
Genome Wide

The common neurodegenerative disorder of the central nervous system is multiple sclerosis (MS). It progresses with autoimmune inflammation and demyelination. Molecular basis study of MS pathogenesis is a significant element of field research, leading to new prevention and treatment strategies by defining the genetic association, epigenetic, and environmental risks factor of MS that could provide a predictive method for estimating human predisposition to MS. From a genetic perspective, MS is a complex disorder due to the combination of genetic and non-genetic factors. The main histocompatibility complex (MHC) is the only universal genetic site associated with MS, and it has been approved for many years. The most common risk for MS in most populations is human leukocyte antigen (HLA) at 6p21. Before the advent of genome-wide association studies (GWASs) encouraging finding new susceptibility loci, other genetic factors in the MS remained uncommon. In this literature review, we summarized details, including references, abstracts, and full text of journal articles. These details were selected and obtained from virtual databases such as Medline and PubMed. Using the keywords and health descriptors in MS, GWAS, IL7R and HLA genes for published data from 2007 until 2019.So, the purpose of this research was to perform an analysis of recent progress in identifying genetic factors and gene polymorphism that affect the risk of MS and how these results explain the disease pathogenesis.

scholarly journals A More Homogeneous Phenotype in Parkinson's Disease Related to R1441G Mutation in the LRRK2 Gene

2021 ◽  
Vol 12 ◽  
Author(s):  
Ana Vinagre-Aragón ◽  
David Campo-Caballero ◽  
Elisabet Mondragón-Rezola ◽  
Lara Pardina-Vilella ◽  
Haizea Hernandez Eguiazu ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Association Studies ◽  
Significant Risk ◽  
Lewy Bodies ◽  
Genome Wide Association Studies ◽  
Clinical Heterogeneity ◽  
Therapeutic Implications ◽  
Genome Wide ◽  
Number Of Patients

Parkinson's disease (PD) is characterized by a great clinical heterogeneity. Nevertheless, the biological drivers of this heterogeneity have not been completely elucidated and are likely to be complex, arising from interactions between genetic, epigenetic, and environmental factors. Despite this heterogeneity, the clinical patterns of monogenic forms of PD have usually maintained a good clinical correlation with each mutation once a sufficient number of patients have been studied. Mutations in LRRK2 are the most commonly known genetic cause of autosomal dominant PD known to date. Furthermore, recent genome-wide association studies have revealed variations in LRRK2 as significant risk factors also for the development of sporadic PD. The LRRK2-R1441G mutation is especially frequent in the population of Basque ascent based on a possible founder effect, being responsible for almost 50% of cases of familial PD in our region, with a high penetrance. Curiously, Lewy bodies, considered the neuropathological hallmark of PD, are absent in a significant subset of LRRK2-PD cases. Indeed, these cases appear to be associated with a less aggressive primarily pure motor phenotype. The aim of our research is to examine the clinical phenotype of R1441G-PD patients, more homogeneous when we compare it with sporadic PD patients or with patients carrying other LRRK2 mutations, and reflect on the value of the observed correlation in the genetic forms of PD. The clinical heterogeneity of PD leads us to think that there may be as many different diseases as the number of people affected. Undoubtedly, genetics constitutes a relevant key player, as it may significantly influence the phenotype, with differences according to the mutation within the same gene, and not only in familial PD but also in sporadic forms. Thus, extending our knowledge regarding genetic forms of PD implies an expansion of knowledge regarding sporadic forms, and this may be relevant due to the future therapeutic implications of all forms of PD.

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