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

Anthony Giampetruzzi; Eric W Danielson; Valentina Gumina; Maryangel Jeon; Sivakumar Boopathy; Robert H Brown; Antonia Ratti; John E Landers; Claudia Fallini

doi:10.1038/s41467-019-11837-y

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

Nat Commun. 2019 Aug 23;10(1):3827. doi: 10.1038/s41467-019-11837-y.

Authors

Anthony Giampetruzzi¹, Eric W Danielson¹, Valentina Gumina², Maryangel Jeon¹, Sivakumar Boopathy¹, Robert H Brown¹, Antonia Ratti^{2

3}, John E Landers¹, Claudia Fallini⁴

Affiliations

¹ Department of Neurology, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
² Istituto Auxologico Italiano, IRCCS, Department of Neurology - Stroke Unit and Laboratory of Neuroscience, Milan, Italy.
³ Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy.
⁴ Department of Neurology, University of Massachusetts Medical School, Worcester, MA, 01605, USA. [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Video-Audio Media

MeSH terms

Acrylamides / pharmacology
Actins / metabolism*
Actins / ultrastructure
Active Transport, Cell Nucleus / drug effects
Active Transport, Cell Nucleus / genetics
Amyotrophic Lateral Sclerosis / genetics
Amyotrophic Lateral Sclerosis / pathology*
Biopsy
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
C9orf72 Protein / genetics
C9orf72 Protein / metabolism
Cell Line
Cerebral Cortex / cytology
Cerebral Cortex / pathology
Embryo, Mammalian
Fibroblasts
Humans
Microscopy, Electron, Transmission
Motor Neurons / cytology
Motor Neurons / pathology*
Mutation
Nuclear Pore / drug effects
Nuclear Pore / pathology*
Nuclear Pore / ultrastructure
Primary Cell Culture
Profilins / genetics
Profilins / metabolism*
Protein Multimerization / drug effects
Protein Multimerization / genetics
Skin / cytology
Skin / pathology
Thiazoles / pharmacology
Thiazolidines / pharmacology

Substances

Acrylamides
Actins
Bridged Bicyclo Compounds, Heterocyclic
C9orf72 Protein
C9orf72 protein, human
KPT-276
PFN1 protein, human
Profilins
Thiazoles
Thiazolidines
latrunculin A

Abstract

Publication types

MeSH terms

Substances

Grants and funding