Objective: The aim of the study was to analyze potential pathogenicity of the PARK2 p.Ala82Glu mutation, by functional studies of Parkin in the mitophagy paradigm system.

Background: Heterozygous mutation carriers in PARK2 gene are observed among Parkinson’s disease (PD) patients twice as much than in healthy controls. The exact mechanism of this phenomenon still remains unclear. The heterozygous p.Ala82Glu mutation identified in PD patients’ is classified as VUS or PD risk variant. In cohort of 627 Polish patients we identified this variant in heterozygous state in 6 patients diagnosed as PD/atypical parkinsonism, to whom the pathogenic mutation in other PD-related genes were excluded (WES analysis, MLPA).

Method: Functional analysis of the PARK2 p.Ala82Glu variant was performed in an established HeLa cell model. Wild type or mutant Parkin cDNA was expressed in cells using pEGFP-C1 and pcDNA-FLAG vector and functionally assessed by western blotting and high content imaging. The analysis was performed before and upon treatment with the inhibitor of oxidative phosphorylation CCCP.

Results: The PARK2 p.Ala82Glu variant showed no major defects in mitochondrial stress-induced activation or enzymatic activity as assessed by Parkin translocation, ubiquitin charging of the catalytic residue, or formation of phosphorylated poly-ubiquitin chains.

Conclusion: Relaying on obtained data of functional analyses performed in the mitophagy paradigm system we conclude that PARK2 p.Ala82Glu mutation has no dramatic function on of the early steps of the PINK1-Parkin mitophagy pathway.
*results partially presented during XXIV World Congress on Parkinson‘s Disease and Related Disorders

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MDS Abstracts - https://www.mdsabstracts.org/abstract/park2-p-ala82glu-variant-is-not-associated-with-parkinsons-disease/