@article{eb107d1dd9d24af08daf1c319c525a3c,
title = "Valosin-containing protein (VCP/p97) inhibitors relieve mitofusin-dependent mitochondrial defects due to VCP disease mutants",
abstract = "Missense mutations of valosin-containing protein (VCP) cause an autosomal dominant disease known as inclusion body myopathy, Paget disease with frontotemporal dementia (IBMPFD) and other neurodegenerative disorders. The pathological mechanism of IBMPFD is not clear and there is no treatment. We show that endogenous VCP negatively regulates Mitofusin, which is required for outer mitochondrial membrane fusion. Because 90% of IBMPFD patients have myopathy, we generated an in vivo IBMPFD model in adult Drosophila muscle, which recapitulates disease pathologies. We show that common VCP disease mutants act as hyperactive alleles with respect to regulation of Mitofusin. Importantly, VCP inhibitors suppress mitochondrial defects, muscle tissue damage and cell death associated with IBMPFD models in Drosophila. These inhibitors also suppress mitochondrial fusion and respiratory defects in IBMPFD patient fibroblasts. These results suggest that VCP disease mutants cause IBMPFD through a gain-of-function mechanism, and that VCP inhibitors have therapeutic value.",
author = "Ting Zhang and Prashant Mishra and Hay, {Bruce A.} and David Chan and Ming Guo",
note = "Funding Information: We are grateful to the support of the Natalie R and Eugene S Jones Fund in Aging and Neurodegenerative Disease Research. We would like to thank Hansong Deng for first noting the suppression of PINK1 mutant phenotype by VCP overexpression, Dr. Tzu Kang Sang from the National Tsing Hua University, Taiwan, for the VCP disease mutants allele flies, Dr. Hugo Bellen from the Baylor College of Medicine for the kind gift of pCasper-Mfn-HA flies, Dr. CK Yao from Academia Sinica, Taipei, for pCasper-Mfn-eGFP construct and Dr. Frank A Laski for the microtome usage. Ellison Medical Foundation Senior Scholar award Ming Guo Bruce A. Hay. McKnight Endowment Fund for Neuroscience Ming Guo. Glenn Family Foundation Ming Guo. National Institutes of HealthNIA R01 Ming Guo. National Institutes of HealthNINDS EUREKA award Ming Guo. Natalie R. and Eugene S. Jones Ming Guo Fund in Aging and Neurodegenerative Disease Research. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Publisher Copyright: {\textcopyright} Zhang et al.",
year = "2017",
month = mar,
day = "21",
doi = "10.7554/eLife.17834",
language = "English (US)",
volume = "6",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}