Modulation of actin polymerization affects nucleocytoplasmic transport in multiple forms of Amyotrophic Lateral Sclerosis
Anthony Giampetruzzi, Eric W. Danielson, Maryangel Jeon, Valentia Gumina, Sivakumar Boopathy, Robert H. Brown, John E. Landers, Claudia Fallini
Received Date: 11th September 2018
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 expansions, the most common mutations in ALS patients. Collectively, our data link NCT defects to ALS-associated pathology and propose the regulation of actin homeostasis as a novel therapeutic strategy for ALS and other neurodegenerative diseases.
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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.