title: Autophagy regulates amyotrophic lateral sclerosis-linked fused in sarcoma-positive stress granules in neurons.
abstract: Mutations in fused in sarcoma (FUS), a DNA/RNA binding protein, have been associated with familial amyotrophic lateral sclerosis (fALS), which is a fatal neurodegenerative disease that causes progressive muscular weakness and has overlapping clinical and pathologic characteristics with frontotemporal lobar degeneration. However, the role of autophagy in regulation of FUS-positive stress granules (SGs) and aggregates remains unclear. We found that the ALS-linked FUS(R521C) mutation causes accumulation of FUS-positive SGs under oxidative stress, leading to a disruption in the release of FUS from SGs in cultured neurons. Autophagy controls the quality of proteins or organelles; therefore, we checked whether autophagy regulates FUS(R521C)-positive SGs. Interestingly, FUS(R521C)-positive SGs were colocalized to RFP-LC3-positive autophagosomes. Furthermore, FUS-positive SGs accumulated in atg5(-/-) mouse embryonic fibroblasts (MEFs) and in autophagy-deficient neurons. However, FUS(R521C) expression did not significantly impair autophagic degradation. Moreover, autophagy activation with rapamycin reduced the accumulation of FUS-positive SGs in an autophagy-dependent manner. Rapamycin further reduced neurite fragmentation and cell death in neurons expressing mutant FUS under oxidative stress. Overall, we provide a novel pathogenic mechanism of ALS associated with a FUS mutation under oxidative stress, as well as therapeutic insight regarding FUS pathology associated with excessive SGs.
authors.affiliation: Department of Biotechnology and Biological Sciences, Hannam University, Daejeon, Korea; Department of Life Science, Chung-Ang University, Seoul, Korea.
authors.forename: Hyun-Hee
authors.initials: HH
authors.lastname: Ryu
authors.affiliation: Department of Biotechnology and Biological Sciences, Hannam University, Daejeon, Korea.
authors.forename: Mi-Hee
authors.initials: MH
authors.lastname: Jun
authors.affiliation: Department of Biotechnology and Biological Sciences, Hannam University, Daejeon, Korea.
authors.forename: Kyung-Jin
authors.initials: KJ
authors.lastname: Min
authors.affiliation: Department of Applied Biology, Kyungpook National University, Kyungbuk, Korea.
authors.forename: Deok-Jin
authors.initials: DJ
authors.lastname: Jang
authors.affiliation: Department of Life Science, Chung-Ang University, Seoul, Korea. Electronic address: yongseok@cau.ac.kr.
authors.forename: Yong-Seok
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Department of Medicine and Microbiology, Chungbuk National University, Cheongju, Korea. Electronic address: hkkim69@chungbuk.ac.kr.
authors.forename: Hyong Kyu
authors.initials: HK
authors.lastname: Kim
authors.affiliation: Department of Biotechnology and Biological Sciences, Hannam University, Daejeon, Korea. Electronic address: leeja@hnu.kr.
authors.forename: Jin-A
authors.initials: JA
authors.lastname: Lee
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D003594:Cytoplasmic Granules / Q000235:genetics* / Q000473:pathology*; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000473:pathology; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress / Q000235:genetics* / Q000502:physiology*; D034702:RNA-Binding Protein FUS / Q000235:genetics* / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology
chemical_list: C000599551:FUS protein, mouse; D034702:RNA-Binding Protein FUS; D020123:Sirolimus
keywords: ALS; Autophagy; FUS; Oxidative stress; Stress granule