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Time-Lapse Video Microscopy for Assessment of EYFP-Parkin Aggregation as a Marker for Cellular Mitophagy
Published on: May 4, 2016
The parkin V380L variant is a genetic modifier of Machado-Joseph disease with impact on mitophagy
Jonasz J Weber1,2, Leah Czisch1, Priscila Pereira Sena1
1Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076, Tübingen, Germany.
Abstract:
Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative spinocerebellar ataxia caused by a polyglutamine-coding CAG repeat expansion in the ATXN3 gene. While the CAG length correlates negatively with the age at onset, it accounts for approximately 50% of its variability only. Despite larger efforts in identifying contributing genetic factors, candidate genes with a robust and plausible impact on the molecular pathogenesis of MJD are scarce. Therefore, we analysed missense single nucleotide polymorphism variants in the PRKN gene encoding the Parkinson's disease-associated E3 ubiquitin ligase parkin, which is a well-described interaction partner of the MJD protein ataxin-3, a deubiquitinase. By performing a correlation analysis in the to-date largest MJD cohort of more than 900 individuals, we identified the V380L variant as a relevant factor, decreasing the age at onset by 3 years in homozygous carriers. Functional analysis in an MJD cell model demonstrated that parkin V380L did not modulate soluble or aggregate levels of ataxin-3 but reduced the interaction of the two proteins. Moreover, the presence of parkin V380L interfered with the execution of mitophagy-the autophagic removal of surplus or damaged mitochondria-thereby compromising cell viability. In summary, we identified the V380L variant in parkin as a genetic modifier of MJD, with negative repercussions on its molecular pathogenesis and disease age at onset.
Insights
The Parkinson
Area of Science:
- Neurogenetics
- Molecular Pathogenesis
- Neurodegenerative Diseases
Background:
- Machado-Joseph disease (MJD) is an inherited spinocerebellar ataxia linked to ATXN3 gene CAG repeat expansions.
- CAG repeat length influences MJD onset but explains only half of the variability.
- Identifying additional genetic modifiers for MJD is crucial for understanding its pathogenesis.
Purpose of the Study:
- To investigate the role of single nucleotide polymorphism (SNP) variants in the PRKN gene as potential modifiers of MJD.
- To analyze the impact of parkin (PRKN) variants on MJD age at onset and molecular mechanisms.
Main Methods:
- Correlation analysis of PRKN gene variants in over 900 MJD patients.
- Functional studies in an MJD cell model to assess protein interactions and cellular processes.
- Evaluation of parkin V380L variant's effect on ataxin-3 levels, protein interactions, and mitophagy.
Main Results:
- The PRKN V380L variant was identified as a significant factor, reducing MJD age at onset by 3 years in homozygous carriers.
- Parkin V380L did not alter soluble or aggregated ataxin-3 levels but decreased the interaction between parkin and ataxin-3.
- The V380L variant impaired mitophagy, negatively affecting cell viability.
Conclusions:
- The parkin V380L variant acts as a genetic modifier of Machado-Joseph disease.
- This variant negatively impacts MJD's molecular pathogenesis and reduces the age of disease onset.
- PRKN variants represent potential therapeutic targets for MJD.
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