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Early-Onset Parkinsons Disease Is a Mitochondrial Disease: A Nigral Mitochondrial Cytopathy

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Technical Report,15 Aug 2017,14 Aug 2018

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Mayo Clinic Jacksonville Jacksonville United States

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Loss of function mutations in the genes encoding PINK1 and Parkin results in early-onset forms of Parkinsons disease EOPD. Both enzymes are functionally linked and together direct a neuroprotective mitochondrial qualitycontrol 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 PINK1Parkin pathwayby 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.

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  • Medicine and Medical Research

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