Pathogenic VCPTER94 Alleles Are Dominant Actives and Contribute to Neurodegeneration by Altering Cellular ATP Level in a Drosophila IBMPFD Model 英文参考文献.docVIP

PathogenicVCP/TER94AllelesAreDominantActivesand ContributetoNeurodegenerationbyAlteringCellular ATPLevelinaDrosophilaIBMPFDModel Ya-ChuChang1.,Wan-TzuHung1.,Yun-ChinChang1,HenryC.Chang2,Chia-LinWu1,3 ,Ann-Shyn Chiang1,3,GeorgeR.Jackson4,5,6,Tzu-KangSang1,3 * 1 Institute of Biotechnology, Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan,2 Department of Biological Sciences, Purdue University, West Lafayette, Indiana, United States of America, 3 Brain Research Center, National Tsing Hua University, Hsinchu, Taiwan, 4 Department of Neurology, Neuroscience, and Cell Biology, University of Texas Medical Branch, Galveston, Texas, United States of America,5 Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, United States of America,6 Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, Texas, United States of America Abstract Inclusion body myopathy with Paget’s disease of bone and frontotemporal dementia (IBMPFD) is caused by mutations in Valosin-containing protein (VCP), a hexameric AAA ATPase that participates in a variety of cellular processes such as protein degradation, organelle biogenesis, and cell-cycle regulation. To understand how VCP mutations cause IBMPFD, we have established aDrosophila model by overexpressing TER94 (the soleDrosophila VCP ortholog) carrying mutations analogous to those implicated in IBMPFD. Expression of these TER94 mutants in muscle and nervous systems causes tissue degeneration, recapitulating the pathogenic phenotypes in IBMPFD patients. TER94-induced neurodegenerative defects are enhanced by elevated expression of wild-type TER94, suggesting that the pathogenic alleles are dominant active mutations. This conclusion is further supported by the observation that TER94-induced neurodegenerative defects r