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 ‘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.
Highlights
Abnormal mitochondrial function is a key process in the pathogenesis of Parkinson’s disease (PD)
The Parkinson’s Progression Markers Initiative (PPMI) cohort (n = 540) was comprised of 172 controls and 368 people with PD (PwP). This cohort was dominated by males (65.7% of controls, 65.5% PwP), with controls having a mean age of 61.6 years and those with PD having a mean age of 61.8 years
TOMM40 plays an essential role in mitochondrial import and mitophagy, and the ‘523’ polymorphism has been associated with age of onset of Alzheimer’s disease (AD) and with age-related cognitive decline
Summary
Abnormal mitochondrial function is a key process in the pathogenesis of Parkinson’s disease (PD). Altered or abnormally functioning TOM40, mediated by genetic changes or atypical protein expression, is thought to contribute to mitochondrial dysfunction and protein accumulation in Alzheimer’s disease (AD) and PD8 This may occur through different mechanisms: (1) mitochondrial import impairment, which may prevent essential proteins and peptides from reaching their designated mitochondrial targets, or allow unwanted and mutant proteins to aggregate in the mitochondria; or (2) mitophagy disruption, which may enable damaged and malfunctioning mitochondria to accumulate. This study investigated the distribution of ‘523’ alleles and their association with disease risk and age of symptom onset in two independent PD cohorts, one Australian and one international (the Parkinson’s Progression Markers Initiative, PPMI), using PCR-based and whole genome sequencing approaches
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