Journal
NEURON
Volume 102, Issue 2, Pages 339-+Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2019.02.038
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Funding
- NIH [R01-NS27036, P40-NS047101, F32-AG059358]
- Nomis Foundation
- Muscular Dystrophy Association
- Target ALS
- ALS Association
- Human Frontiers Science Program (HFSP) long-term fellowship
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While cytoplasmic aggregation of TDP-43 is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia, how aggregates form and what drives its nuclear clearance have not been determined. Here we show that TDP-43 at its endogenous level undergoes liquid-liquid phase separation (LLPS) within nuclei in multiple cell types. Increased concentration of TDP-43 in the cytoplasm or transient exposure to sonicated amyloid-like fibrils is shown to provoke long-lived liquid droplets of cytosolic TDP-43 whose assembly and maintenance are independent of conventional stress granules. Cytosolic liquid droplets of TDP-43 accumulate phosphorylated TDP-43 and rapidly convert into gels/ solids in response to transient, arsenite-mediated stress. Cytoplasmic TDP-43 droplets slowly recruit importin-oc and Nup62 and induce mislocalization of RanGaol, Ran, and Nup107, thereby provoking inhibition of nucleocytoplasmic transport, clearance of nuclear TDP-43, and cell death. These findings identify a neuronal cell death mechanism that can be initiated by transient-stress-induced cytosolic de-mixing of TDP-43.
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