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.

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 An Increased Burden of Highly Active Retrotransposition Competent L1s Is Associated with Parkinson’s Disease Risk and Progression in the PPMI Cohort

2020 ◽  
Vol 21 (18) ◽  
pp. 6562 ◽  
Author(s):  
Abigail L. Pfaff ◽  
Vivien J. Bubb ◽  
John P. Quinn ◽  
Sulev Koks
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Risk ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Highly Active ◽  
Germline Variation ◽  
Progression Markers ◽  
Long Interspersed Element

Long interspersed element-1 (LINE-1/L1s) contributes 17% of the human genome with more than 1 million elements present; however, fewer than 100 of these have evidence for being retrotransposition competent (RC). In addition to those RC-L1s present in the reference genome, there are a small number of known non-reference L1 insertions that are also retrotransposition competent. L1 activity, whether through the potentially detrimental effects of their mRNA or protein expression or somatic retrotransposition events, has been linked to several neurological conditions. The polymorphic nature of both reference and non-reference RC-L1s in terms of their presence or absence will result in individuals harboring a different combination of these elements and it is currently unknown if this type of germline variation contributes to the risk of neurological disease. Here, we utilized whole-genome sequencing data from 178 healthy controls and 372 Parkinson’s disease (PD) subjects from the Parkinson’s Progression Markers Initiative (PPMI) to investigate the role of RC-L1s in PD. In the PPMI cohort, we identified 22 reference and 50 non-reference polymorphic RC-L1 loci. Focusing on 16 highly active RC-L1 loci, an increased burden of these elements (≥9) was associated with PD (OR 1.25, 95% CI 1.03–1.51, p = 0.02). In addition, we identified significant associations of progression markers of PD and the burden of highly active RC-L1s. This study has identified a novel type of genetic element associated with PD risk and disease progression.

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 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 SNCAGene, but NotMAPT, Influences Onset Age of Parkinson’s Disease in Chinese and Australians

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Yue Huang ◽  
Gang Wang ◽  
Dominic Rowe ◽  
Ying Wang ◽  
John B. J. Kwok ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Age Of Onset ◽  
Age At Onset ◽  
Research Network ◽  
Onset Age ◽  
Entire Cohort ◽  
Protein Tau ◽  
Chinese Cohort ◽  
Australian Cohort

Background.α-Synuclein (SNCA) and microtubule-associated protein tau (MAPT) are the two major genes independently, but not jointly, associated with susceptibility for Parkinson’s disease (PD). TheSNCAgene has recently been identified as a major modifier of age of PD onset. WhetherMAPTgene synergistically influences age of onset of PD is unknown.Objective. To investigate independent and joint effects ofMAPTandSNCAon PD onset age.Methods. 412 patients with PD were recruited from the Australian PD Research Network (123) and the Neurology Department, Ruijin Hospital Affiliated to Shanghai Jiaotong University, China (289).MAPT(rs17650901) tagging H1/H2 haplotype andSNCA(Rep1) were genotyped in the Australian cohort, andMAPT(rs242557, rs3744456) andSNCA(rs11931074, rs894278) were genotyped in the Chinese cohort. SPSS regression analysis was used to test genetic effects on age at onset of PD in each cohort.Results.SNCApolymorphisms associated with the onset age of PD in both populations.MAPTpolymorphisms did not enhance such association in either entire cohort.Conclusion. This study suggests that, in both ethnic groups,SNCAgene variants influence the age at onset of PD andα-synuclein plays a key role in the disease course of PD.

scholarly journals Familial Parkinson's Disease: Possible Role of Environmental Factors

1987 ◽  
Vol 14 (3) ◽  
pp. 303-305 ◽  
Author(s):  
Susan Calne ◽  
Bruce Schoenberg ◽  
Wayne Martin ◽  
Ryan J. Uitti ◽  
Peter Spencer ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Age Of Onset ◽  
Mean Difference ◽  
Environmental Damage ◽  
Age Related ◽  
Children And Parents ◽  
The Central Nervous System ◽  
The Mean

ABSTRACT:We report here six families with Parkinson's disease in whom the onset of symptoms tended to occur at approximately the same time irrespective of the age of the patient. The mean difference in the time of onset in different generations was 4.6 years while the mean difference in age of onset in children and parents was 25.2 years. We construe this pattern of age separation within families as suggestive of an environmental rather than genetic cause. Support for this view derives from the lack of correlation between occurrence of the disease and the degree of consanguinity. We conclude that our findings are in accord with the hypothesis which attributes the cause of some cases of Parkinson's disease to early, subclinical environmental damage followed by age-related attrition of neurons within the central nervous system.

scholarly journals Gene Therapy for Parkinson’s Disease Associated with GBA1 Mutations

2021 ◽  
pp. 1-6
Author(s):  
Asa Abeliovich ◽  
Franz Hefti ◽  
Jeffrey Sevigny
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Clinical Trials ◽  
Disease Risk ◽  
Age Of Onset ◽  
Normal Range ◽  
Genetic Studies ◽  
Lysosomal Dysfunction ◽  
The Brain

Human genetic studies as well as studies in animal models indicate that lysosomal dysfunction plays a key role in the pathogenesis of Parkinson’s disease. Among the lysosomal genes involved, GBA1, has the largest impact on Parkinson’s disease risk. Deficiency in the GBA1 encoded enzyme glucocerebrosidase (GCase) leads to the accumulation of the GCase glycolipid substrates glucosylceramide and glucosylsphingosine and ultimately results in toxicity and inflammation and negatively affect many aspects of Parkinson’s disease, including disease risk, the severity of presentation, age of onset, and likelihood of progression to dementia. These findings support the view that re-establishing normal range levels of GCase expression and enzyme activity may reduce the progression of Parkinson’s disease in patients carrying GBA1 mutations. Studies in mouse models indicate that PR001, a rAAV9 vector-based gene therapy designed to deliver a functional GBA1 gene to the brain, suggest that this therapeutic approach may slow or stop disease progression. PR001 is currently being evaluated in clinical trials with Parkinson’s disease patients carrying GBA1 mutations.

scholarly journals Sex- and age‐dependent alterations of splenic immune cell profile and NK cell phenotypes and function in C57BL/6J mice

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Kelly B. Menees ◽  
Rachael H. Earls ◽  
Jaegwon Chung ◽  
Janna Jernigan ◽  
Nikolay M. Filipov ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Sex Differences ◽  
Nk Cells ◽  
Immune Cell ◽  
Nk Cell ◽  
Spleen Weight ◽  
Age Related ◽  
And Function ◽  
Cell Phenotypes

Abstract Background Physiological homeostasis decline, immunosenescence, and increased risk for multiple diseases, including neurodegeneration, are all hallmarks of ageing. Importantly, it is known that the ageing process is sex-biased. For example, there are sex differences in predisposition for multiple age-related diseases, including neurodegenerative and autoimmune diseases. However, sex differences in age-associated immune phenotypes are not clearly understood. Results Here, we examined the effects of age on immune cell phenotypes in both sexes of C57BL/6J mice with a particular focus on NK cells. We found female-specific spleen weight increases with age and concordant reduction in the number of splenocytes per gram of spleen weight compared to young females. To evaluate sex- and age-associated changes in splenic immune cell composition, we performed flow cytometry analysis. In male mice, we observed an age-associated reduction in the frequencies of monocytes and NK cells; female mice displayed a reduction in B cells, NK cells, and CD8 + T cells and increased frequency of monocytes and neutrophils with age. We then performed a whole blood stimulation assay and multiplex analyses of plasma cytokines and observed age- and sex-specific differences in immune cell reactivity and basal circulating cytokine concentrations. As we have previously illustrated a potential role of NK cells in Parkinson’s disease, an age-related neurodegenerative disease, we further analyzed age-associated changes in NK cell phenotypes and function. There were distinct differences between the sexes in age-associated changes in the expression of NK cell receptors, IFN-γ production, and impairment of α-synuclein endocytosis. Conclusions This study demonstrates sex- and age-specific alterations in splenic lymphocyte composition, circulating cytokine/chemokine profiles, and NK cell phenotype and effector functions. Our data provide evidence that age-related physiological perturbations differ between the sexes which may help elucidate sex differences in age-related diseases, including neurodegenerative diseases, particularly Parkinson’s disease, where immune dysfunction is implicated in their etiology.

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