Abstract
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 language | English (US) |
|---|---|
| Pages (from-to) | 5059-5068 |
| Number of pages | 10 |
| Journal | Human molecular genetics |
| Volume | 25 |
| Issue number | 23 |
| DOIs | |
| State | Published - 2016 |
Funding
We thank Dr Xinnan Wang (Stanford University), Dr Ming Guo (University of California, Los Angeles), Drs Yongqing Zhang, Aiyu Yao and Li Liu (CAS) for generously providing reagents and valuable suggestions in live imaging studies. We thank members of the Wu lab for stimulating discussions and helpful suggestions. We thank Dr Eileen Bigio, Warren McGee and other members of the Wu group for critical reading of the manuscript. We are grateful for generous help from Drs C Wang, D Han and J Xie at National Center for Nanoscience and Technology in our SEM work. National Major Basic Research Program of China (2013CB917803 to M.C., L.Z. and J.L.; 2013CB531301 to Q.X.); the National Natural Science Foundation of China (91132710 to M.C., L.Z. and J.L.; 31430048 to Q.X.); CAMS-I2M (2006I2M1004 to Q.X.); NIH (R01NS084412 and R01MH080378 to B.L.; R56NS074763 and RO1AG033004 to J.Y.W.); ALS Therapy Alliance (R01AG054008 to J.Y.W.).
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Genetics(clinical)