{Reference Type}: Journal Article
{Title}: The parkin V380L variant is a genetic modifier of Machado-Joseph disease with impact on mitophagy.
{Author}: Weber JJ;Czisch L;Pereira Sena P;Fath F;Huridou C;Schwarz N;Incebacak Eltemur RD;Würth A;Weishäupl D;Döcker M;Blumenstock G;Martins S;Sequeiros J;Rouleau GA;Jardim LB;Saraiva-Pereira ML;França MC;Gordon CR;Zaltzman R;Cornejo-Olivas MR;van de Warrenburg BPC;Durr A;Brice A;Bauer P;Klockgether T;Schöls L;Riess O; ;Schmidt T;
{Journal}: Acta Neuropathol
{Volume}: 148
{Issue}: 1
{Year}: 2024 Aug 1
{Factor}: 15.887
{DOI}: 10.1007/s00401-024-02762-6
{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.