Early-Onset Parkinsons Disease Is a Mitochondrial Disease: A Nigral Mitochondrial Cytopathy
Abstract
Loss of function mutations in the genes encoding PINK1 and Parkin results in early-onset forms of Parkinson's disease (EOPD). Both enzymes are functionally linked and together direct a neuroprotective mitochondrial quality control (mitoQC) ensuring elimination of damaged organelles from cells via the autophagy-lysosome system (i.e.mitophagy), which is lost in EOPD. Given the complexity of this pathway and the general missing heritability in EOPD, it is highly likely that additional genes regulating this pathway may also be found mutated in EOPD. The overarching goals of this project are to 1) identify high confidence genetic modifiers of the PINK1/Parkin pathway by a two-tiered functional screening (overlay of genome-wide siRNA and miRNA screens) in cells, 2) to identify the underlying genetic variation and characterize the EOPD genome (whole-genome-sequencing of patients), as well as 3) to determine the pathogenicity of these novel EOPD sequence variants in functional readout studies. Using this combined functional genetics approach we are currently whole-genome sequencing the first 50 EOPD patients and overlaying results from our sequences with hits from the siRNA and miRNA screens.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2018
- Accession Number
- AD1060917
Entities
People
- Owen A. Ross
Organizations
- Mayo Clinic Hospital – Jacksonville