title: The homozygote VCP(R¹⁵⁵H/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 (VCP(R155H/R155H)) model carrying the common R155H mutations, which develops many clinical features typical of the VCP-associated human diseases. Homozygote VCP(R155H/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 VCP(R155H/R155H) mice manifest prominent muscle, heart, brain and spinal cord pathology, including striking mitochondrial abnormalities, in addition to disrupted autophagy and ubiquitin pathologies. The VCP(R155H/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.
authors.affiliation: Department of Pediatrics, University of California Irvine, Irvine, California, United States of America.
authors.forename: Angèle
authors.initials: A
authors.lastname: Nalbandian
authors.forename: Katrina J
authors.initials: KJ
authors.lastname: Llewellyn
authors.forename: Masashi
authors.initials: M
authors.lastname: Kitazawa
authors.forename: Hong Z
authors.initials: HZ
authors.lastname: Yin
authors.forename: Mallikarjun
authors.initials: M
authors.lastname: Badadani
authors.forename: Negar
authors.initials: N
authors.lastname: Khanlou
authors.forename: Robert
authors.initials: R
authors.lastname: Edwards
authors.forename: Christopher
authors.initials: C
authors.lastname: Nguyen
authors.forename: Jogeshwar
authors.initials: J
authors.lastname: Mukherjee
authors.forename: Tahseen
authors.initials: T
authors.lastname: Mozaffar
authors.forename: Giles
authors.initials: G
authors.lastname: Watts
authors.forename: John
authors.initials: J
authors.lastname: Weiss
authors.forename: Virginia E
authors.initials: VE
authors.lastname: Kimonis
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D018703:Founder Effect; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055879:Gene Knock-In Techniques; D006720:Homozygote; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009132:Muscles / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018979:Myositis, Inclusion Body / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010001:Osteitis Deformans / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017354:Point Mutation; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse