Transitional endoplasmic reticulum ATPase

VCP (Valosin-Containing Protein), also known as Transitional Endoplasmic Reticulum ATPase, is an AAA-ATPase essential for multiple cellular processes including ER-to-Golgi vesicular transport, ER-associated protein degradation (ERAD), mitotic spindle disassembly, autophagy maturation, and DNA damage response (UniProt: P55072). The protein functions within multi-protein complexes to extract and unfold ubiquitinated substrates from membranes and chromatin for proteasomal or autophagic degradation, and regulates stress granule dynamics.

VCP mutations cause several neurodegenerative conditions, including Inclusion Body Myopathy with Paget Disease and Frontotemporal Dementia (IBMPFD1), Frontotemporal Dementia and/or Amyotrophic Lateral Sclerosis 6 (FTDALS6), and Charcot-Marie-Tooth Disease Type 2Y (CMT2Y) (UniProt: P55072). These conditions underscore VCP's critical role in neuronal proteostasis and cellular homeostasis.

In Alzheimer's Disease, VCP is significantly down-regulated in post-mortem AD brain tissue compared to age-matched controls, with a mean log2 fold-change of −0.274 (Chaparral AD proteomics). This reduction may impair ER quality control, autophagy-mediated clearance, and mitochondrial protein homeostasis—processes implicated in AD pathogenesis. The downregulation could contribute to accumulation of misfolded proteins and cellular stress characteristic of AD neurodegeneration.