期刊
ACTA NEUROPATHOLOGICA
卷 138, 期 1, 页码 67-84出版社
SPRINGER
DOI: 10.1007/s00401-019-01998-x
关键词
Amyotrophic lateral sclerosis; FUS; Induced pluripotent stem cells; RNA-binding proteins; Phase transition; Protein homeostasis
资金
- Deutsche Forschungsgemeinschaft (DFG)
- CRTD, part of the TUD
- DFG Research Center [DFG FZT 111]
- Cluster of Excellence (DFG) [EXC 168]
- Hans und Ilse Breuer Stiftung
- Humboldt Foundation [3.5-INI/1155756 STP]
- European Union's Horizon 2020 research and innovation program [643417]
- Bundesministerium fur Bildung und Forschung [01ED1601A, 01ED1601B]
- Bundesministerium fur Bildung und Forschung
- Israel, Ministry of Health
- Italy, Ministero dell'Istruzione dell'Universita e della Ricerca
- Sweden, Swedish Research Council
- Switzerland, Swiss National Science Foundation
- Robert Packard Center for ALS at Johns Hopkins
- Max Planck Society
- European Research Council [725836]
- USA National Institutes of Health [R01NS081303, R21NS100055, R21NS098379, R21NS094921]
- Muscular Dystrophy Association
- German Motor Neuron Disease Network (BMBF-MND-Net) [360644]
- EU Joint Program Neurodegenerative Diseases (JPND)
- Interdisciplinary Centre for Clinical Research (IZKF Aachen) [N7-4]
- German Myopathy Society (DGM)
- Initiative Therapieforschung ALS e.V.
- Petermax-Muller-Stiftung
Amyotrophic lateral sclerosis (ALS) is a lethal disease characterized by motor neuron degeneration and associated with aggregation of nuclear RNA-binding proteins (RBPs), including FUS. How FUS aggregation and neurodegeneration are prevented in healthy motor neurons remain critically unanswered questions. Here, we use a combination of ALS patient autopsy tissue and induced pluripotent stem cell-derived neurons to study the effects of FUS mutations on RBP homeostasis. We show that FUS' tendency to aggregate is normally buffered by interacting RBPs, but this buffering is lost when FUS mislocalizes to the cytoplasm due to ALS mutations. The presence of aggregation-prone FUS in the cytoplasm causes imbalances in RBP homeostasis that exacerbate neurodegeneration. However, enhancing autophagy using small molecules reduces cytoplasmic FUS, restores RBP homeostasis and rescues motor function in vivo. We conclude that disruption of RBP homeostasis plays a critical role in FUS-ALS and can be treated by stimulating autophagy.
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