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Autophagy regulates amyotrophic lateral sclerosis-linked fused in sarcoma-positive stress granules in neurons.
- Source :
-
Neurobiology of aging [Neurobiol Aging] 2014 Dec; Vol. 35 (12), pp. 2822-2831. Date of Electronic Publication: 2014 Jul 27. - Publication Year :
- 2014
-
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.<br /> (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Autophagy drug effects
Cells, Cultured
Female
Frontotemporal Lobar Degeneration genetics
Frontotemporal Lobar Degeneration pathology
Gene Expression Regulation
Genetic Association Studies
Humans
Male
Mice
Neurons cytology
Neurons metabolism
RNA-Binding Protein FUS metabolism
Sirolimus pharmacology
Amyotrophic Lateral Sclerosis genetics
Amyotrophic Lateral Sclerosis pathology
Autophagy physiology
Cytoplasmic Granules genetics
Cytoplasmic Granules pathology
Mutation
Neurons pathology
Oxidative Stress genetics
Oxidative Stress physiology
RNA-Binding Protein FUS genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1558-1497
- Volume :
- 35
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Neurobiology of aging
- Publication Type :
- Academic Journal
- Accession number :
- 25216585
- Full Text :
- https://doi.org/10.1016/j.neurobiolaging.2014.07.026