Valosin-containing protein (VCP/p97) inhibitors relieve Mitofusin-dependent mitochondrial defects due to VCP disease mutants.
Missense mutations ofvalosin-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 anin vivoIBMPFD model in adultDrosophilamuscle, 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 inDrosophila. 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.
Department of Neurology, UCLA David Geffen School of Medicine, University of California, Los Angele, United States.
Ting
0000-0002-9636-6554
T
Zhang
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
Prashant
0000-0003-2223-1742
P
Mishra
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
Bruce A
BA
Hay
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
David
0000-0002-0191-2154
D
Chan
Department of Neurology, UCLA David Geffen School of Medicine, University of California, Los Angele, United States.|Department of Molecular and Medical Pharmacology, UCLA David Geffen School of Medicine, University of California, Los Angeles, United States.
Ming
M
Guo
D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005347:Fibroblasts / Q000502:physiology; D057180:Frontotemporal Dementia / Q000503:physiopathology*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D049288:Muscular Dystrophies, Limb-Girdle / Q000503:physiopathology*; D050505:Mutant Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018979:Myositis, Inclusion Body / Q000503:physiopathology*; D010001:Osteitis Deformans / Q000503:physiopathology*; D016896:Treatment Outcome; D000074405:Valosin Containing Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; C527117:Marf protein, Drosophila; D008565:Membrane Proteins; D050505:Mutant Proteins; D000074405:Valosin Containing Protein
D. melanogaster; degenerative disease; human; mitochondria; neuroscience; therapeutic treatment