DNA methylation-based surrogates of plasma proteins are associated with Parkinson's disease risk

AbstractEvidence for epigenetic regulation playing a role in Parkinson’s disease (PD) is growing, particularly for DNA modifications. Approximately 90% of PD cases are due to a complex interaction between age, genes, and environmental factors, and epigenetic marks are thought to mediate the relationship between aging, genetics, the environment, and disease risk. To date, there are a small number of published genome-wide studies of DNA modifications in PD, but none accounted for cell-type or sex in their analyses. Given the hetereogeneity of bulk brain tissue samples and known sex differences in PD risk, progression, and severity, these are critical variables to account for. In this first genome-wide analysis of DNA methylation in an enriched neuronal population from PD post-mortem parietal cortex, we report sex-specific PD-associated methylation changes in PARK7 (DJ-1), SLC17A6 (VGLUT2), PTPRN2 (IA-2β), NR4A2 (NURR1), and other genes involved in developmental pathways, neurotransmitter packaging and release, and axon and neuron projection guidance.

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Faculty Opinions recommendation of RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717993395.793473738 ◽

2013 ◽

Author(s):

Doug Galasko

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Disease Risk ◽

Protein Sorting

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

Scientific Reports ◽

10.1038/s41598-021-85510-0 ◽

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.

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