Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-019-11837-y
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Funding
- American ALS Association [15-PDF-210, 18-IIA418, 18-PDF-423]
- National Institute of Health/NINDS [F32 NS090831, R01 NS073873]
- National Institute of Health/NCRR [S10RR027897, S10OD021580]
- Doctorate School of Molecular and Translational Medicine, Universita degli Studi di Milano
- Fondazione Regionale per la Ricerca Biomedica (FRRB), Regione Lombardia [2015-0023]
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of unknown etiology. Although defects in nucleocytoplasmic transport (NCT) may be central to the pathogenesis of ALS and other neurodegenerative diseases, the molecular mechanisms modulating the nuclear pore function are still largely unknown. Here we show that genetic and pharmacological modulation of actin polymerization disrupts nuclear pore integrity, nuclear import, and downstream pathways such as mRNA post-transcriptional regulation. Importantly, we demonstrate that modulation of actin homeostasis can rescue nuclear pore instability and dysfunction caused by mutant PFN1 as well as by C9ORF72 repeat expansion, the most common mutation in ALS patients. Collectively, our data link NCT defects to ALS-associated cellular pathology and propose the regulation of actin homeostasis as a novel therapeutic strategy for ALS and other neurodegenerative diseases.
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