VCP is a critical component for TDP-43 disaggregase activity in skeletal muscle
- 1Washington University School of Medicine
Abstract
TDP-43 aggregates are a unifying pathological feature between several neurodegenerative diseases and myopathies. Mutations in the AAA ATPase protein VCP have been linked to TDP-43 proteinopathies in both brain and skeletal muscle including frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and inclusion body myopathy (IBM). In the case of multisystem proteinopathy (MSP), patients with VCP mutations may present with combinations of these phenotypes. Of these MSP phenotypes IBM is the most common, affecting around 90% of patients. However, it is not well understood how mutations in VCP contribute to the accumulation of insoluble TDP-43 aggregates in the context of skeletal muscle. To study this further, we used in vitro and in vivo models of TDP-43 aggregation in skeletal muscle in the presence of VCP mutation or inhibition to study its effects on the ability to clear TDP-43 aggregates. Across multiple model systems we found that VCP disease mutations or inhibition causes a reduced capacity to clear insoluble TDP-43, suggesting a VCP loss of function in patients with VCP-related MSP.
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BibTeX
@misc{lynch2026critical,
title = {{VCP is a critical component for TDP-43 disaggregase activity in skeletal muscle}},
author = {E. M. Lynch and S. K. Pittman and J. Daw and C. C. Weihl},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.14.751559},
url = {https://www.biorxiv.org/content/10.64898/2026.09.14.751559v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - VCP is a critical component for TDP-43 disaggregase activity in skeletal muscle
AU - E. M. Lynch
AU - S. K. Pittman
AU - J. Daw
AU - C. C. Weihl
PY - 2026
DA - 2026/09/14
PB - bioRxiv
DO - 10.64898/2026.09.14.751559
UR - https://www.biorxiv.org/content/10.64898/2026.09.14.751559v1
AB - TDP-43 aggregates are a unifying pathological feature between several neurodegenerative diseases and myopathies. Mutations in the AAA ATPase protein VCP have been linked to TDP-43 proteinopathies in both brain and skeletal muscle including frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and inclusion body myopathy (IBM). In the case of multisystem proteinopathy (MSP), patients with VCP mutations may present with combinations of these phenotypes. Of these MSP phenotypes IBM is the most common, affecting around 90% of patients. However, it is not well understood how mutations in VCP contribute to the accumulation of insoluble TDP-43 aggregates in the context of skeletal muscle. To study this further, we used in vitro and in vivo models of TDP-43 aggregation in skeletal muscle in the presence of VCP mutation or inhibition to study its effects on the ability to clear TDP-43 aggregates. Across multiple model systems we found that VCP disease mutations or inhibition causes a reduced capacity to clear insoluble TDP-43, suggesting a VCP loss of function in patients with VCP-related MSP.
ER -