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RNA polymerase II-associated proteins reveal pathways affected in VCP-related amyotrophic lateral sclerosis

Rafiee, Mahmoud-Reza; Rohban, Sara; Davey, Karen; Ule, Jernej; Luscombe, Nicholas M; (2023) RNA polymerase II-associated proteins reveal pathways affected in VCP-related amyotrophic lateral sclerosis. Brain , 146 (6) pp. 2547-2556. 10.1093/brain/awad046. Green open access

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Abstract

Valosin-containing protein (VCP) is a hexameric ATPase associated with diverse cellular activities. Genetic mutations in VCP are associated with several forms of muscular and neuronal degeneration, including amyotrophic lateral sclerosis (ALS). Moreover, VCP mediates UV-induced proteolysis of RNA polymerase II (RNAPII), but little is known about the effects of VCP mutations on the transcriptional machinery. Here, we used silica particle-assisted chromatin enrichment and mass spectrometry to study proteins co-localized with RNAPII in precursor neurons differentiated from VCP-mutant or control induced pluripotent stem cells. Remarkably, we observed diminished RNAPII binding of proteins involved in transcription elongation and mRNA splicing in mutant cells. One of these is SART3, a recycling factor of the splicing machinery, whose knockdown leads to perturbed intron retention in several ALS-associated genes. Additional reduced proteins are RBM45, EIF5A and RNF220, mutations in which are associated with various neurodegenerative disorders and are linked to TDP-43 aggregation. Conversely, we observed increased RNAPII binding of heat shock proteins such as HSPB1. Together, these findings shed light on how transcription and splicing machinery are impaired by VCP mutations, which might contribute to aberrant alternative splicing and proteinopathy in neurodegeneration.

Type: Article
Title: RNA polymerase II-associated proteins reveal pathways affected in VCP-related amyotrophic lateral sclerosis
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/brain/awad046
Publisher version: https://doi.org/10.1093/brain/awad046
Language: English
Additional information: Copyright © The Author(s) 2023. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: RNA polymerase II, SPACE, proteomics, ALS, VCP
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10167735
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