The Homozygote VCPR155H/R155H Mouse Model Exhibits Accelerated Human VCP-Associated Disease Pathology

Abstract

Valosin containing protein (VCP) mutations are the cause of hereditary inclusion body myopathy, Paget's disease of bone, frontotemporal dementia (IBMPFD). VCP gene mutations have also been linked to 2% of isolated familial amyotrophic lateral sclerosis (ALS). VCP is at the intersection of disrupted ubiquitin proteasome and autophagy pathways, mechanisms responsible for the intracellular protein degradation and abnormal pathology seen in muscle, brain and spinal cord. We have developed the homozygous knock-in VCP mouse (VCPR155H/R155H) model carrying the common R155H mutations, which develops many clinical features typical of the VCP-associated human diseases. Homozygote VCPR155H/R155H mice typically survive less than 21 days, exhibit weakness and myopathic changes on EMG. MicroCT imaging of the bones reveal non-symmetrical radiolucencies of the proximal tibiae and bone, highly suggestive of PDB. The VCPR155H/R155H mice manifest prominent muscle, heart, brain and spinal cord pathology, including striking mitochondrial abnormalities, in addition to disrupted autophagy and ubiquitin pathologies. The VCPR155H/R155H homozygous mouse thus represents an accelerated model of VCP disease and can be utilized to elucidate the intricate molecular mechanisms involved in the pathogenesis of VCP-associated neurodegenerative diseases and for the development of novel therapeutic strategies.

Activation of the NLRP3 Inflammasome Is Associated with Valosin-Containing Protein Myopathy

“…Thus, the remainder of the study was conducted using our unique VCP R155H/+ heterozygote experimental mouse model, which features clinical characteristics that closely mimics human VCP-associated myopathy [27, 34, 35]. Altogether, these results from immunocytochemistry, Western blotting and flow cytometry corroborate to confirm activation of the NLRP3 inflammasome in human VCP myoblasts and that this activation can be significantly downregulated following in vitro treatment with the MCC950 Inhibitor.…”

Valosin-containing protein (VCP/p97) inhibitors relieve Mitofusin-dependent mitochondrial defects due to VCP disease mutants

“…These were not observed in wildtype or VCP WT flies (Figure 4G–H’’’). Importantly, the pathologies observed in flight muscle at day 6 post eclosion were not present at day 2 (Figure 4—figure supplement 1), suggesting the degenerative nature of the pathology, as with the human disease and mouse models (Kimonis et al, 2008a; Custer et al, 2010; Nalbandian et al, 2012). Together, these observations indicate that IFM-specific expression of VCP RH and AE recapitulates a broad spectrum of IBMPFD disease pathologies and forms the strong basis for further investigation of disease mechanisms and treatment studies.

10.7554/eLife.17834.010Figure 4.Expression of VCP disease mutants and mfn RNAi knocking down lead to pathology in adult muscle tissue.( A ) Diagram of Human p97/VCP protein domains and two disease mutants, VCP R155H and A232E.

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VCP cooperates with UBXD1 to degrade mitochondrial outer membrane protein MCL1 in model of Huntington's disease

“…Mutations in the VCP gene are associated with several neurodegenerative diseases and causes mitochondrial dysfunction. Mice with homozygous pathogenic VCP mutations displayed mitochondrial abnormalities [46]. Fibroblasts derived from patients with VCP mutations exhibited mitochondrial depolarization and depletion of ATP content [47].…”