BIOLOGY & BIOTECHNOLOGY SEMINAR
"The role of the cytoskeleton and nucleocytoplasmic transport in the pathogenesis of ALS"
~ BBT Neurobiology Faculty Candidate ~
Claudia Fallini, Research Assistant Professor
Department of Neurology
University of Massachusetts Medical School
Amyotrophic lateral sclerosis (ALS) is an adult-onset fatal neurodegenerative disease characterized by the loss of motor neurons (MNs). Recent findings from several groups point at defects in nucleocytoplasmic transport as central to ALS pathology. Our research focuses on understanding how dysregulation on cytoskeletal structures caused by ALS-causing mutations in the actin-binding protein PFN1 leads to MN degeneration. Our data show that genetic and pharmacological modulation of actin polymerization disrupts the integrity and function of the nuclear pore, the gateway for protein transport in and out of the nucleus, causing defects to downstream pathways such as mRNA 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 nucleocytoplasmic transport defects to ALS-associated pathology and propose the regulation of actin homeostasis as a novel therapeutic strategy for ALS and other neurodegenerative diseases.
Tuesday, February 5, 2019, 4:15 p.m.