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

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

doi:10.1038/s41467-019-11837-y

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.

Highlights

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of unknown etiology
To investigate whether mutant PFN1 toxicity is associated with nucleocytoplasmic transport (NCT) defects, we examined its effects on the distribution of essential factors controlling this process
No difference in the overall levels of the tested nucleoporins was observed in all conditions, while a slight reduction in Ran levels was present in PFN1C71G motor neurons (MNs) (Supplementary Fig. 4)

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of unknown etiology. 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. 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. 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. Modulating actin homeostasis was able to rescue the NCT defects caused by mutant PFN1 and C9ORF72 repeat expansion, suggesting this pathway could represent a novel therapeutic strategy for ALS

Methods

Results

Conclusion