An embarrassment of riches? Mechanisms underlying VCP neurodegeneration

Article Clinical Neurology

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

Mahmoud-Reza Rafiee et al.

Summary: Valosin-containing protein (VCP) is a hexameric ATPase associated with cellular activities and its mutations are linked to neurodegenerative diseases. The study reveals that VCP mutations impair the binding of transcriptional machinery and mRNA splicing proteins to RNA polymerase II (RNAPII), leading to aberrant alternative splicing and proteinopathy in neurodegeneration.

BRAIN (2023)

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Review Biochemistry & Molecular Biology

Targeting of client proteins to the VCP/p97/Cdc48 unfolding machine

Hemmo Meyer et al.

Summary: The AAA+ ATPase p97 is an important protein unfolding machine that can target client proteins to facilitate degradation or regulation. Different types of adapters, such as Ufd1-Npl4 and SEP-domain adapters, are responsible for targeting clients to p97 through different mechanisms. Despite the different targeting strategies, both pathways converge by inserting the client into the p97 pore to initiate protein unfolding and disassembly processes.

FRONTIERS IN MOLECULAR BIOSCIENCES (2023)

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Review Genetics & Heredity

Development of a standard of care for patients with valosin-containing protein associated multisystem proteinopathy

Manisha Korb et al.

Summary: Valosin-containing protein (VCP) associated multisystem proteinopathy (MSP) is a rare inherited disorder with varying phenotypes. An international consortium of multidisciplinary experts has developed standard of care guidelines for this under-diagnosed disease to aid in timely diagnosis and optimal management.

ORPHANET JOURNAL OF RARE DISEASES (2022)

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Review Biochemistry & Molecular Biology

The functional importance of VCP to maintaining cellular protein homeostasis

Brittany A. Ahlstedt et al.

Summary: This review summarizes recent research on VCP, uncovering surprising new ways of regulation, novel aspects of substrate recognition, and novel pathways and substrates that utilize its activity.

BIOCHEMICAL SOCIETY TRANSACTIONS (2022)

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Article Clinical Neurology

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

F. Wang et al.

Summary: Mutations in p97/VCP have been found to cause two motor neuron diseases. In this study, patient-derived induced pluripotent stem cells were used to generate p97 mutant motor neurons. Proteomic analysis revealed dysregulated protein levels and delayed cell cycle exit in these mutant motor neurons. The study also showed that two p97 inhibitors and a cyclin-dependent kinase 4/6 inhibitor could rescue motor neuron death. This research provides valuable insights into the pathogenesis of motor neuron diseases and potential therapeutic targets.

BRAIN COMMUNICATIONS (2022)

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Article Clinical Neurology

TDP-43 and FUS mislocalization in VCP mutant motor neurons is reversed by pharmacological inhibition of the VCP D2 ATPase domain

Jasmine Harley et al.

Summary: RNA binding proteins play a key role in the pathogenesis of ALS, with VCP mutations causing mislocalization of RBPs. The study revealed that enhanced function of the D2 ATPase domain in VCP mutant neurons drives mislocalization of TDP-43 and FUS.

BRAIN COMMUNICATIONS (2021)

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Article Multidisciplinary Sciences