Vcp Conditional Knockout mouse models

The AAA+ ATPase p97, encoded by mouse Vcp and orthologous to human VCP, is a homohexameric segregase with an N domain plus tandem D1 and D2 ATPase rings that threads ubiquitinated substrates through its central pore, extracting them from membranes, chromatin, and multiprotein complexes. Cofactors assign function: UFD1 and NPL4 direct ER-associated degradation and ribosome quality control, p47 supports membrane fusion, and UBXD1 and others govern lysosomal and mitochondrial quality control plus autophagosome maturation. Dominant missense mutations, mostly at the N to D1 interface such as R155H and R191Q, cause multisystem proteinopathy, namely inclusion body myopathy with Paget disease and frontotemporal dementia, plus ALS14, by increasing ATPase activity and altering cofactor binding rather than ablating function. Constitutive Vcp null is embryonic lethal while heterozygous nulls are largely normal, so patient knockins at the endogenous locus are the correct allele; use conditional alleles with muscle or neuronal Cre for tissue-specific proteostasis endpoints.

A floxed Vcp allele paired with Cre gives spatial control that whole body knockouts cannot offer. People use it to separate developmental roles from adult homeostasis, to model somatic mutations, and to match disease that begins in one organ.