期刊
NATURE CELL BIOLOGY
卷 24, 期 9, 页码 1378-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41556-022-00988-8
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资金
- NIH [R01 NS27036, P41 GM103533]
- Nomis Foundation
- Target ALS [20134792]
- National Institute of Neurological Diseases and Stroke [NIH R01NS088578, NS047101]
- Kraatz Family/Nicholas Martin Jr Family Foundation
- National Science Foundation [DGE-1650112]
- ALS Association [21-PDF-583]
- UCSD School of Medicine Microscopy Core grant [P30 NS047101]
This study identifies HSPB1 as a regulator of cytoplasmic TDP-43 phase separation and aggregation, and suggests that decreased HSPB1 may be involved in the pathogenesis of ALS and other neurodegenerative diseases.
While acetylated, RNA-binding-deficient TDP-43 reversibly phase separates within nuclei into complex droplets (anisosomes) comprised of TDP-43-containing liquid outer shells and liquid centres of HSP70-family chaperones, cytoplasmic aggregates of TDP-43 are hallmarks of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here we show that transient oxidative stress, proteasome inhibition or inhibition of the ATP-dependent chaperone activity of HSP70 provokes reversible cytoplasmic TDP-43 de-mixing and transition from liquid to gel/solid, independently of RNA binding or stress granules. Isotope labelling mass spectrometry was used to identify that phase-separated cytoplasmic TDP-43 is bound by the small heat-shock protein HSPB1. Binding is direct, mediated through TDP-43's RNA binding and low-complexity domains. HSPB1 partitions into TDP-43 droplets, inhibits TDP-43 assembly into fibrils, and is essential for disassembly of stress-induced TDP-43 droplets. A decrease in HSPB1 promotes cytoplasmic TDP-43 de-mixing and mislocalization. HSPB1 depletion was identified in spinal motor neurons of patients with ALS containing aggregated TDP-43. These findings identify HSPB1 to be a regulator of cytoplasmic TDP-43 phase separation and aggregation. Lu et al. report that biomolecular condensation of cytoplasmic TDP-43 is regulated by HSPB1 to maintain its droplets in liquid and not gel/solid structures and that HSPB1 is decreased in spinal motor neurons with TDP-43 pathology in patients with amyotrophic lateral sclerosis.
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