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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 <jats:italic>PRKN<\/jats:italic> 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\u00a0years 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\u2014the autophagic removal of surplus or damaged mitochondria\u2014thereby 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.<\/jats:p>","DOI":"10.1007\/s00401-024-02762-6","type":"journal-article","created":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T06:02:37Z","timestamp":1722492157000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The parkin V380L variant is a genetic modifier of Machado\u2013Joseph disease with impact on mitophagy"],"prefix":"10.1007","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3758-1569","authenticated-orcid":false,"given":"Jonasz J.","family":"Weber","sequence":"first","affiliation":[]},{"given":"Leah","family":"Czisch","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2061-5470","authenticated-orcid":false,"given":"Priscila","family":"Pereira Sena","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6564-4291","authenticated-orcid":false,"given":"Florian","family":"Fath","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1796-8240","authenticated-orcid":false,"given":"Chrisovalantou","family":"Huridou","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5170-9656","authenticated-orcid":false,"given":"Natasa","family":"Schwarz","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2522-6562","authenticated-orcid":false,"given":"Rana D.","family":"Incebacak Eltemur","sequence":"additional","affiliation":[]},{"given":"Anna","family":"W\u00fcrth","sequence":"additional","affiliation":[]},{"given":"Daniel","family":"Weish\u00e4upl","sequence":"additional","affiliation":[]},{"given":"Miriam","family":"D\u00f6cker","sequence":"additional","affiliation":[]},{"given":"Gunnar","family":"Blumenstock","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3720-2920","authenticated-orcid":false,"given":"Sandra","family":"Martins","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9846-1037","authenticated-orcid":false,"given":"Jorge","family":"Sequeiros","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8403-1418","authenticated-orcid":false,"given":"Guy A.","family":"Rouleau","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6907-5068","authenticated-orcid":false,"given":"Laura Bannach","family":"Jardim","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3905-9563","authenticated-orcid":false,"given":"Maria-Luiza","family":"Saraiva-Pereira","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0898-2419","authenticated-orcid":false,"suffix":"Jr.","given":"Marcondes C.","family":"Fran\u00e7a","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1576-214X","authenticated-orcid":false,"given":"Carlos R.","family":"Gordon","sequence":"additional","affiliation":[]},{"given":"Roy","family":"Zaltzman","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6313-5680","authenticated-orcid":false,"given":"Mario R.","family":"Cornejo-Olivas","sequence":"additional","affiliation":[]},{"given":"Bart P. 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