UMMS Affiliation
Department of Neurology
Publication Date
2019-08-23
Document Type
Article
Disciplines
Amino Acids, Peptides, and Proteins | Genetic Phenomena | Molecular and Cellular Neuroscience | Nervous System Diseases | Nucleic Acids, Nucleotides, and Nucleosides
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.
Keywords
Amyotrophic lateral sclerosis, Molecular neuroscience
Rights and Permissions
Copyright © The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
DOI of Published Version
10.1038/s41467-019-11837-y
Source
Nat Commun. 2019 Aug 23;10(1):3827. doi: 10.1038/s41467-019-11837-y. Link to article on publisher's site
Journal/Book/Conference Title
Nature communications
Related Resources
PubMed ID
31444357
Repository Citation
Giampetruzzi A, Danielson EW, Gumina V, Jeon M, Boopathy S, Brown RH, Ratti A, Landers JE, Fallini C. (2019). Modulation of actin polymerization affects nucleocytoplasmic transport in multiple forms of amyotrophic lateral sclerosis. Open Access Publications by UMMS Authors. https://doi.org/10.1038/s41467-019-11837-y. Retrieved from https://escholarship.umassmed.edu/oapubs/3959
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Included in
Amino Acids, Peptides, and Proteins Commons, Genetic Phenomena Commons, Molecular and Cellular Neuroscience Commons, Nervous System Diseases Commons, Nucleic Acids, Nucleotides, and Nucleosides Commons