PINK1 and Parkin are genetic modifiers for FUS-induced neurodegeneration

Yanbo Chen, Jianwen Deng, Peng Wang, Mengxue Yang, Xiaoping Chen, Li Zhu, Jianghong Liu, Bingwei Lu, Yan Shen, Kazuo Fushimi, Qi Xu, Jane Y. Wu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


Dysregulation of Fused in Sarcoma (FUS) gene expression is associated with fronto-temporal lobar degeneration (FTLD), and missense mutations in the FUS gene have been identified in patients affected by amyotrophic lateral sclerosis (ALS). However, molecular and cellular defects underlying FUS proteinopathy remain to be elucidated. Here, we examined whether genes important for mitochondrial quality control play a role in FUS proteinopathy. In our genetic screening, Pink1 and Park genes were identified as modifiers of neurodegeneration phenotypes induced by wild type (Wt) or ALS-associated P525Lmutant human FUS. Down-regulating expression of either Pink1 or Parkin genes ameliorated FUS-induced neurodegeneration phenotypes. The protein levels of PINK1 and Parkin were elevated in cells overexpressing FUS. Remarkably, ubiquitinylation of Miro1 protein, a downstream target of the E3 ligase activity of Parkin, was also increased in cells overexpressing FUS protein. In fly motor neurons expressing FUS, both motility and processivity of mitochondrial axonal transport were reduced by expression of either Wt- or P525L-mutant FUS. Finally, down-regulating PINK1 or Parkin partially rescued the locomotive defects and enhanced the survival rate in transgenic flies expressing FUS. Our data indicate that PINK1 and Parkin play an important role in FUS-induced neurodegeneration. This study has uncovered a previously unknown link between FUS proteinopathy and PINK1/Parkin genes, providing new insights into the pathogenesis of FUS proteinopathy.

Original languageEnglish (US)
Pages (from-to)5059-5068
Number of pages10
JournalHuman molecular genetics
Issue number23
StatePublished - 2016

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics
  • Molecular Biology


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