Open AccessThe Homozygote VCPR155H/R155H Mouse Model Exhibits Accelerated Human VCP-Associated Disease Pathology
Author(s) -
Angèle Nalbandian,
Katrina J. Llewellyn,
Masashi Kitazawa,
Hong Yin,
Mallikarjun Badadani,
Négar Khanlou,
Robert A. Edwards,
Christopher Nguyen,
Jogeshwar Mukherjee,
Tahseen Mozaffar,
G.F. Watts,
John H. Weiss,
Virginia Kimonis
Publication year - 2012
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0046308
Subject(s) - amyotrophic lateral sclerosis , pathology , medicine , autophagy , frontotemporal dementia , neurodegeneration , spinal cord , ubiquitin , pathogenesis , c9orf72 , biology , disease , dementia , neuroscience , gene , genetics , apoptosis
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.