scholarly journals Identification of an age-related Parkinson's disease risk factor that regulates sulfur metabolism

2021 ◽  
Author(s):  
Shong Lau ◽  
Shani Stern ◽  
Sara Linker ◽  
Ioana Da Silva ◽  
Nako Nakatsuka ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Risk Factor ◽  
Disease Risk ◽  
Neuronal Degeneration ◽  
Sulfur Metabolism ◽  
Embryonic Stem ◽  
Energy Deficiency ◽  
Age Related ◽  
Anti Oxidant

Abstract Human aging is the main risk factor for Parkinson’s disease (PD). To better understand age-related PD pathogenesis, we modeled PD with directly reprogrammed dopaminergic neurons (iDA) which preserve donor aging signatures. By transcriptome analysis and immunohistochemistry on postmortem tissues, we identified a sulfurtransferase, TSTD1, to be upregulated in aged and diseased individuals. TSTD1 catalyzes sulfur transfer from thiosulfate to glutathione (GSH). GSH and cysteine were significantly decreased in dopaminergic (DA) neurons with TSTD1 overexpression. Lower intracellular H2S levels and mitochondrial membrane potential (MMP) were identified in aged, PD iDA, and TSTD1 overexpressing embryonic stem cell (ES)-derived DA neurons. TSTD1 overexpression could lead to GAPDH inhibition and energy deficiency in neurons. We hypothesize that TSTD1 upregulation in aged and PD individuals could disrupt sulfur metabolism which compromises anti-oxidant capacity and energy production in neurons; both of these mechanisms have been implicated as triggers for DA neuronal degeneration in PD.

scholarly journals The TOMM40 ‘523’ polymorphism in disease risk and age of symptom onset in two independent cohorts of Parkinson’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Megan C. Bakeberg ◽  
Madison E. Hoes ◽  
Anastazja M. Gorecki ◽  
Frances Theunissen ◽  
Abigail L. Pfaff ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Symptom Onset ◽  
Disease Risk ◽  
Age Of Onset ◽  
Sequencing Analysis ◽  
Age Related ◽  
Australian Cohort ◽  
Progression Markers ◽  
Age Related Cognitive Decline

AbstractAbnormal mitochondrial function is a key process in the pathogenesis of Parkinson’s disease (PD). The central pore-forming protein TOM40 of the mitochondria is encoded by the translocase of outer mitochondrial membrane 40 homologue gene (TOMM40). The highly variant ‘523’ poly-T repeat is associated with age-related cognitive decline and age of onset in Alzheimer’s disease, but whether it plays a role in modifying the risk or clinical course of PD it yet to be elucidated. The TOMM40 ‘523’ allele length was determined in 634 people with PD and 422 healthy controls from an Australian cohort and the Parkinson’s Progression Markers Initiative (PPMI) cohort, using polymerase chain reaction or whole genome sequencing analysis. Genotype and allele frequencies of TOMM40 ‘523’ and APOE ε did not differ significantly between the cohorts. Analyses revealed TOMM40 ‘523’ allele groups were not associated with disease risk, while considering APOE ε genotype. Regression analyses revealed the TOMM40 S/S genotype was associated with a significantly later age of symptom onset in the PPMI PD cohort, but not after correction for covariates, or in the Australian cohort. Whilst variation in the TOMM40 ‘523’ polymorphism was not associated with PD risk, the possibility that it may be a modifying factor for age of symptom onset warrants further investigation in other PD populations.

A closer look at FBXO41 as a Parkinson's disease risk factor

2013 ◽  
Vol 19 (12) ◽  
pp. 1175-1176 ◽  
Author(s):  
Cillian R. King ◽  
Sophie van der Sluis ◽  
Tinca J. Polderman ◽  
Ruud F. Toonen
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Risk Factor ◽  
Disease Risk ◽  
Disease Risk Factor

scholarly journals MITOCHONDRIAL-DERIVED PEPTIDE, SHLP2, A NOVEL PROTECTIVE FACTOR IN PARKINSON’S DISEASE

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S838-S838
Author(s):  
Su Jeong Kim ◽  
Anjali Devgan ◽  
Hemal H Mehta ◽  
Pinchas Cohen
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protective Factor ◽  
Disease Risk ◽  
Therapeutic Potential ◽  
Age Related ◽  
Wide Range ◽  
Induced Apoptosis ◽  
Mtdna Variants ◽  
Mtdna Snp

Abstract Mitochondrial DNA (mtDNA) variants are associated with a wide range of diseases of aging, from diabetes to Alzheimer’s, as well as with longevity itself. However, to date, little work has thoroughly examined the functional roles of mtDNA variants in such age-related diseases or the therapeutic potential of mitochondrial-derived peptides (MDPs) in these conditions. Our lab hypothesizes that mtDNA SNPs could affect MDPs, and we recently showed that a mtDNA SNP is associated with reduced circulating levels of an MDP called humanin and with cognitive decline. How other mtDNA SNPs affect MDPs and disease risk has yet to be analyzed. Remarkably, a recent paper showed a mtDNA SNP (m.2158 T>C) reduces the risk of Parkinson’s disease (PD). Of note, this SNP changes lysine (K) 4 to arginine (R) of a MDP called SHLP2, which is encoded by the 16S rRNA region of the mtDNA. SHLP2 acts as a neuroprotective factor and as a metabolic regulator. We hypothesized that K4R SHLP2 – produced by individuals who carry mtDNA m.2158 T>C – is a protective factor for Parkinson’s disease. Cycloheximide-treated pulse-chase experiments additionally showed that K4R SHLP2 is more stable than WT SHLP2. WT SHLP2 has a polyubiquitination whereas K4R SHLP2 diminish the polyubiquitination. K4R SHLP2 more potently inhibits PD toxin (MPP+) induced apoptosis in neuronal cells. K4R SHLP2 reverse the mitochondrial membrane potential loss and mitochondria respiration defect in TFAM heterozygous knockout MEFs. Altogether, SHLP2 has the therapeutic potential as a precision medicine in PD.

scholarly journals The TOMM40 ‘523’ polymorphism in disease risk and age of symptom onset in two independent cohorts of Parkinson’s disease.

2020 ◽  
Author(s):  
Megan Bakeberg ◽  
Madison Hoes ◽  
Anastazja Gorecki ◽  
Frances Theunissen ◽  
Abigail Pfaff ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Symptom Onset ◽  
Disease Risk ◽  
Age Of Onset ◽  
Sequencing Analysis ◽  
Age Related ◽  
Australian Cohort ◽  
Progression Markers ◽  
Age Related Cognitive Decline

Abstract Abnormal mitochondrial function is a key process in the pathogenesis of Parkinson’s disease (PD). The central pore-forming protein TOM40 of the mitochondria is encoded by the translocase of outer mitochondrial membrane 40 homologue gene (TOMM40). The highly variant poly-T repeat is associated with age-related cognitive decline and age of onset in Alzheimer’s disease, but whether it plays a role in modifying the risk or clinical course of PD it yet to be elucidated. The TOMM40 allele length was determined in 634 people with PD and 422 healthy controls from an Australian cohort and the Parkinson’s Progression Markers Initiative (PPMI) cohort, using polymerase chain reaction or whole genome sequencing analysis. Genotype and allele frequencies of TOMM40 and APOE ε did not differ significantly between the cohorts. Analyses revealed TOMM40 groups were not associated with disease risk, while considering APOE ε genotype. Regression analyses revealed the TOMM40 S/S genotype was associated with a significantly later age of symptom onset in the PPMI PD cohort, but not in the Australian cohort. Variation in the TOMM40 structural variant was not associated with PD risk, but may be a modifying factor for age of symptom onset in some PD populations, warranting further investigation.

scholarly journals Genetic Modifiers of Pathogenic LRRK2 G2019S Neurodegeneration in Drosophila

2018 ◽  
Author(s):  
Sierra Lavoy ◽  
Vinita G. Chittoor-Vinod ◽  
Clement Y. Chow ◽  
Ian Martin
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Variation ◽  
Genome Wide Association Study ◽  
Neuronal Degeneration ◽  
Pathogenic Mutation ◽  
Genetic Modifiers ◽  
Age Related ◽  
A Genome ◽  
Lrrk2 G2019s

AbstractDisease phenotypes can be highly variable among individuals with the same pathogenic mutation. There is increasing evidence that background genetic variation is a strong driver of disease variability in addition to the influence of environment. To understand the genotype-phenotype relationship that determines the expressivity of a pathogenic mutation, a large number of backgrounds must be studied. This can be efficiently achieved using model organism collections such as the Drosophila Genetic Reference Panel (DGRP). Here, we used the DGRP to assess the variability of locomotor dysfunction in a LRRK2 G2019S Drosophila melanogaster model of Parkinson’s disease. We find substantial variability in the LRRK2 G2019S locomotor phenotype in different DGRP backgrounds. A genome-wide association study for candidate genetic modifiers reveals 177 genes that drive wide phenotypic variation, including 19 top association genes. Genes involved in the outgrowth and regulation of neuronal projections are enriched in these candidate modifiers. RNAi functional testing of the top association and neuronal projection-related genes reveals that pros, pbl, ct and CG33506 significantly modify age-related dopamine neuron loss and associated locomotor dysfunction in the Drosophila LRRK2 G2019S model. These results demonstrate how natural genetic variation can be used as a powerful tool to identify genes that modify disease-related phenotypes. We report novel candidate modifier genes for LRRK2 G2019S that may be used to interrogate the link between LRRK2, neurite regulation and neuronal degeneration in Parkinson’s disease.

scholarly journals Sleep, pain, and neurodegeneration: A Mendelian randomization study

2021 ◽  
Author(s):  
Sandeep Grover ◽  
Manu Sharma ◽  
Keyword(s):  
Multiple Sclerosis ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Risk Factor ◽  
Macular Degeneration ◽  
Mendelian Randomization ◽  
Age Related Macular Degeneration ◽  
Suggestive Evidence ◽  
Age Related

AbstractObjectiveTo examine whether sleep and pain-related traits have a causal effect on the risk of neurodegeneration.DesignTwo-sample Mendelian randomization using an inverse-variance weighted (IVW) estimate of the summary effect estimates.SettingGenetic data on sleep and pain-related traits and neurodegenerative disorders (NDD) from various cohorts comprising individuals predominantly of European ancestry.ParticipantsParticipants from the International Sleep Genetic Epidemiology Consortium (ISGEC), UK Biobank sleep and chronotype research group, International Genomics of Alzheimer’s patients (IGAP), project MinE, International Age-related Macular Degeneration Consortium (IAMDGC), International Multiple Sclerosis Genetics Consortium (IMSGC), International Parkinson’s Disease Genomics Consortium (IPDGC)ExposuresSelf-reported chronotype (CHR), morning preference (MP), insomnia symptoms (INS), sleep duration (SP), short sleep (SS), long sleep (LS), and multisite chronic pain (MCP)Main outcome measuresAge-related macular degeneration (AMD), Alzheimer’s disease (AD), Amyotrophic lateral sclerosis (ALS), Multiple sclerosis (MS), and Parkinson’s disease (PD)ResultsWe considered a threshold of P=0.00142 as significant accounting for multiple testing, and P<0.05 was considered to be suggestive evidence for a potential association. Using direct MR, MP was observed as the strongest risk factor for AMD (ORIVW = 1.19, 95% CI 1.08, 1.32, P = 0.00073). We observed suggestive evidence of influence of different sleep traits on neurodegeneration: CHR on AMD (ORIVW = 1.27, 95% CI 1.08, 1.49, P = 0.0034), SS on AD (ORIVW 1.26, 95% CI 1.08, 1.46, P = 0.0044), and INS on ALS (ORIVW 1.55, 95% CI 1.12, 2.14, P = 0.0123). The association of SS with AD was, however, lost after the exclusion of overlapping UKB samples. Using pain as exposure, our study failed to observe any role of pain in neurodegeneration. Results were largely robust to reverse causal analyses and sensitivity analyses accounting for horizontal pleiotropy.ConclusionsOur study highlighted the role of morning preference as a risk factor for AMD and provided suggestive evidence of different sleep traits on a wide spectrum of neurodegenerative diseases.

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