期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-27221-8
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资金
- ISF (Israel Science foundation) [735/19]
- Ministry of Science and Technology State of Israel [0601166782]
- European Research Council (ERC) [309377]
- Israel Ministry of health JPND program [3-17160]
- Human Frontiers Science Program (HFSP) [RGP0026/2020-102]
- Radala Foundation for ALS Research
- Intramural Research Program of the National Institutes of Neurological Disorders and Stroke, NIH
Mislocalization of TDP-43 in axons of ALS patients leads to the assembly of G3BP1-positive RNP condensates, inhibiting local protein synthesis in distal axons and NMJs.
Mislocalization of the predominantly nuclear RNA/DNA binding protein, TDP-43, occurs in motor neurons of similar to 95% of amyotrophic lateral sclerosis (ALS) patients, but the contribution of axonal TDP-43 to this neurodegenerative disease is unclear. Here, we show TDP-43 accumulation in intra-muscular nerves from ALS patients and in axons of human iPSC-derived motor neurons of ALS patient, as well as in motor neurons and neuromuscular junctions (NMJs) of a TDP-43 mislocalization mouse model. In axons, TDP-43 is hyperphosphorylated and promotes G3BP1-positive ribonucleoprotein (RNP) condensate assembly, consequently inhibiting local protein synthesis in distal axons and NMJs. Specifically, the axonal and synaptic levels of nuclear-encoded mitochondrial proteins are reduced. Clearance of axonal TDP-43 or dissociation of G3BP1 condensates restored local translation and resolved TDP-43-derived toxicity in both axons and NMJs. These findings support an axonal gain of function of TDP-43 in ALS, which can be targeted for therapeutic development.
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