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P97/VCP ATPase inhibitors can rescue p97 mutation-linked motor neuron degeneration

Wang, F. and Li, S. and Wang, T. Y. and Lopez, G. A. and Antoshechkin, I. and Chou, T. F. (2022) P97/VCP ATPase inhibitors can rescue p97 mutation-linked motor neuron degeneration. Brain Communications, 4 (4). Art. No. fcac176. ISSN 2632-1297. PMCID PMC9294923. doi:10.1093/braincomms/fcac176.

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Mutations in p97/VCP cause two motor neuron diseases: inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia and familial amyotrophic lateral sclerosis. How p97 mutations lead to motor neuron degeneration is, however, unknown. Here we used patient-derived induced pluripotent stem cells to generate p97 mutant motor neurons. We reduced the genetic background variation by comparing mutant motor neurons to its isogenic wild type lines. Proteomic analysis reveals that p97R155H/+ motor neurons upregulate several cell cycle proteins at Day 14, but this effect diminishes by Day 20. Molecular changes linked to delayed cell cycle exit are observed in p97 mutant motor neurons. We also find that two p97 inhibitors, CB-5083 and NMS-873, restore some dysregulated protein levels. In addition, two p97 inhibitors and a food and drug administration-approved cyclin-dependent kinase 4/6 inhibitor, Abemaciclib, can rescue motor neuron death. Overall, we successfully used iPSC-derived motor neurons, identified dysregulated proteome and transcriptome and showed that p97 inhibitors rescue phenotypes in this disease model.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Li, S.0000-0002-0829-1821
Antoshechkin, I.0000-0002-9934-3040
Chou, T. F.0000-0003-2410-2186
Additional Information:© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Received August 27, 2021. Revised May 11, 2022. Accepted July 06, 2022. Advance access publication July 6, 2022. The authors would like to thank the anonymous reviewers for constructive criticism. This work was supported with fund from the National Institute of Neurological Disorders and Stroke, R01NS102279. The authors report no competing interests. F Wang, S Li and T Y Wang contributed equally to this work.
Funding AgencyGrant Number
Subject Keywords:amyotrophic lateral sclerosis; motor neuron disease; inclusion body myopathy associated with paget disease of bone and frontotemporal dementia; p97 inhibitor; cell cycle
Issue or Number:4
PubMed Central ID:PMC9294923
Record Number:CaltechAUTHORS:20220722-768560000
Persistent URL:
Official Citation:F Wang, S Li, T Y Wang, G A Lopez, I Antoshechkin, T F Chou, P97/VCP ATPase inhibitors can rescue p97 mutation-linked motor neuron degeneration, Brain Communications, Volume 4, Issue 4, 2022, fcac176,
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:115757
Deposited By: George Porter
Deposited On:26 Jul 2022 21:11
Last Modified:26 Jul 2022 21:11

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