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Modulation of actin polymerization affects nucleocytoplasmic transport in multiple forms of amyotrophic lateral sclerosis

Author

Listed:
  • Anthony Giampetruzzi

    (University of Massachusetts Medical School)

  • Eric W. Danielson

    (University of Massachusetts Medical School)

  • Valentina Gumina

    (Istituto Auxologico Italiano, IRCCS, Department of Neurology – Stroke Unit and Laboratory of Neuroscience)

  • Maryangel Jeon

    (University of Massachusetts Medical School)

  • Sivakumar Boopathy

    (University of Massachusetts Medical School)

  • Robert H. Brown

    (University of Massachusetts Medical School)

  • Antonia Ratti

    (Istituto Auxologico Italiano, IRCCS, Department of Neurology – Stroke Unit and Laboratory of Neuroscience
    Università degli Studi di Milano)

  • John E. Landers

    (University of Massachusetts Medical School)

  • Claudia Fallini

    (University of Massachusetts Medical School)

Abstract

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.

Suggested Citation

  • Anthony Giampetruzzi & Eric W. Danielson & Valentina Gumina & Maryangel Jeon & Sivakumar Boopathy & Robert H. Brown & Antonia Ratti & John E. Landers & Claudia Fallini, 2019. "Modulation of actin polymerization affects nucleocytoplasmic transport in multiple forms of amyotrophic lateral sclerosis," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11837-y
    DOI: 10.1038/s41467-019-11837-y
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