Nucleocytoplasmic mRNA redistribution accompanies RNA binding protein mislocalization in ALS motor neurons and is restored by VCP ATPase inhibition.

Abstract

Amyotrophic lateral sclerosis (ALS) is characterized by nucleocytoplasmic mislocalization of the RNA-binding protein (RBP) TDP-43. However, emerging evidence suggests more widespread mRNA and protein mislocalization. Here, we employed nucleocytoplasmic fractionation, RNA sequencing, and mass spectrometry to investigate the localization of mRNA and protein in induced pluripotent stem cell-derived motor neurons (iPSMNs) from ALS patients with TARDBP and VCP mutations. ALS mutant iPSMNs exhibited extensive nucleocytoplasmic mRNA redistribution, RBP mislocalization, and splicing alterations. Mislocalized proteins exhibited a greater affinity for redistributed transcripts, suggesting a link between RBP mislocalization and mRNA redistribution. Notably, treatment with ML240, a VCP ATPase inhibitor, partially restored mRNA and protein localization in ALS mutant iPSMNs. ML240 induced changes in the VCP interactome and lysosomal localization and reduced oxidative stress and DNA damage. These findings emphasize the link between RBP mislocalization and mRNA redistribution in ALS motor neurons and highlight the therapeutic potential of VCP inhibition.

• Authors: Oliver J Ziff, Jasmine Harley, Yiran Wang, Jacob Neeves, Giulia Tyzack, Fairouz Ibrahim, Mark Skehel, Anob M Chakrabarti, Gavin Kelly, Rickie Patani
• Journal: Neuron (Neuron) Vol. 111 Issue 19 Pg. 3011-3027.e7 (10 04 2023) ISSN: 1097-4199 [Electronic] United States
• PMID: 37480846 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Adenosine Triphosphatases
• RNA, Messenger
• RNA-Binding Proteins
• VCP protein, human
• Valosin Containing Protein

Topics

• Humans
• Amyotrophic Lateral Sclerosis (genetics, metabolism)
• Adenosine Triphosphatases (genetics, metabolism)
• RNA, Messenger (metabolism)
• Motor Neurons (metabolism)
• RNA-Binding Proteins (metabolism)
• Valosin Containing Protein (genetics)