Journal
CELL
Volume 173, Issue 3, Pages 677-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2018.03.002
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Funding
- EMF/AFAR fellowship
- AARF fellowship
- ALSA Milton Safenowitz fellowship
- MGH ECOR Tosteson fellowship
- AHA fellowships
- NIH [T32GM008275, T32GM071339, F31NS079009, R01NS081303, R21NS100055, R21NS094921, R35NS097263, R01NS087227, R01GM069909, R35NS097974, R21NS090205, R01GM099836]
- Target ALS
- Welch Foundation
- UTSW Endowed Scholars Program
- HHMI
- ALS FindingACure
- ALSAC
- ALSA
- MDA
- Packard Center for ALS Research
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RNA-binding proteins (RBPs) with prion-like domains (PrLDs) phase transition to functional liquids, which can mature into aberrant hydrogels composed of pathological fibrils thatunderpin fatal neurodegenerative disorders. Several nuclear RBPs with PrLDs, including TDP-43, FUS, hnRNPA1, and hnRNPA2, mislocalize to cytoplasmic inclusions in neurodegenerative disorders, and mutations in their PrLDs can accelerate fibrillization and cause disease. Here, we establish that nuclear-import receptors (NIRs) specifically chaperone and potently disaggregate wild-type and disease-linked RBPs bearing a NLS. Karyopherin-b2 (also called Transportin-1) engages PY-NLSs to inhibit and reverse FUS, TAF15, EWSR1, hnRNPA1, and hnRNPA2 fibrillization, whereas Importin-a plus Karyopherin-b1 prevent and reverse TDP-43 fibrillization. Remarkably, Karyopherin-b2 dissolves phase-separated liquids and aberrant fibrillar hydrogels formed by FUS and hnRNPA1. In vivo, Karyopherin-b2 prevents RBPs with PY-NLSs accumulating in stress granules, restores nuclear RBPlocalization and function, and rescues degeneration caused by disease-linked FUS and hnRNPA2. Thus, NIRs therapeutically restore RBP homeostasis and mitigate neurodegeneration.
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