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Neurobiol Aging. 2014 Dec;35(12):2822-2831. doi: 10.1016/j.neurobiolaging.2014.07.026. Epub 2014 Jul 27.

Autophagy regulates amyotrophic lateral sclerosis-linked fused in sarcoma-positive stress granules in neurons.

Author information

1
Department of Biotechnology and Biological Sciences, Hannam University, Daejeon, Korea; Department of Life Science, Chung-Ang University, Seoul, Korea.
2
Department of Biotechnology and Biological Sciences, Hannam University, Daejeon, Korea.
3
Department of Applied Biology, Kyungpook National University, Kyungbuk, Korea.
4
Department of Life Science, Chung-Ang University, Seoul, Korea. Electronic address: yongseok@cau.ac.kr.
5
Department of Medicine and Microbiology, Chungbuk National University, Cheongju, Korea. Electronic address: hkkim69@chungbuk.ac.kr.
6
Department of Biotechnology and Biological Sciences, Hannam University, Daejeon, Korea. Electronic address: leeja@hnu.kr.

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.

KEYWORDS:

ALS; Autophagy; FUS; Oxidative stress; Stress granule

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