@article{228e25eef2324272a4863d7b1ff4b5fe,
title = "p53 mediates cellular dysfunction and behavioral abnormalities in Huntington's disease",
abstract = "We present evidence for a specific role of p53 in the mitochondria- associated cellular dysfunction and behavioral abnormalities of Huntington's disease (HD). Mutant huntingtin (mHtt) with expanded polyglutamine (polyQ) binds to p53 and upregulates levels of nuclear p53 as well as p53 transcriptional activity in neuronal cultures. The augmentation is specific, as it occurs with mHtt but not mutant ataxin-1 with expanded polyQ. p53 levels are also increased in the brains of mHtt transgenic (mHtt-Tg) mice and HD patients. Perturbation of p53 by pifithrin-α, RNA interference, or genetic deletion prevents mitochondrial membrane depolarization and cytotoxicity in HD cells, as well as the decreased respiratory complex IV activity of mHtt-Tg mice. Genetic deletion of p53 suppresses neurodegeneration in mHtt-Tg flies and neurobehavioral abnormalities of mHtt-Tg mice. Our findings suggest that p53 links nuclear and mitochondrial pathologies characteristic of HD.",
author = "Bae, \{Byoung Il\} and Hong Xu and Shuichi Igarashi and Masahiro Fujimuro and Nishant Agrawal and Yoichi Taya and Hayward, \{S. Diane\} and Moran, \{Timothy H.\} and Craig Montell and Ross, \{Christopher A.\} and Snyder, \{Solomon H.\} and Akira Sawa",
note = "Funding Information: We thank B. Vogelstein and K.W. Kinzler for providing p53 reporter plasmid, discussion, and critical reading of the manuscript; H.Y. Zoghbi for providing SCA1 lymphoblasts and ataxin-1 plasmids; L.M. Thompson for critical reading of the manuscript; A. Kazantsev for providing N67-104Q-GFP plasmid; M.P. Mattson for providing pifithrin-α and discussion; J.C. Troncoso for providing postmortem HD brain tissues and discussion; X.J. Li for providing His-Htt N171-23Q/120Q plasmids and discussion on purifying mHtt from bacteria; D.R. Borchelt, G. Schilling, E. O{\textquoteright}Hearn, M.E. Molliver, and R.L. Margolis for helpful discussion; L. Hester for neuronal culture; K. Nakaso, Y. Ozeki, and L. Cohen for technical help. B.-I.B. thanks J.-J. Chung and B.S.-J. Bae for unwavering support and encouragement. Supported by USPHS grants, MH-069853 (A.S.), EY08117 (C.M.), DA-00266 (S.H.S.), DA-00074 (S.H.S.); foundation grants (A.S.), Huntington{\textquoteright}s Disease Society for America grant, Hereditary Disease Foundation grant, Stanley, NARSAD award, S-R; Korea Foundation for Advanced Studies Predoctoral Fellowship (B.-I.B). The authors declare that they have no competing financial interests.",
year = "2005",
month = jul,
day = "7",
doi = "10.1016/j.neuron.2005.06.005",
language = "English (US)",
volume = "47",
pages = "29--41",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "1",
}