Hyeon, Seung Jae Park, Jinyoung Yoo, Junsang Kim, Su-Hyun Hwang, Yu Jin Kim, Seung-Chan Liu, Tian Shim, Hyun Soo Kim, Yunha Cho, Yakdol Woo, Jiwan Kim, Key-Sun Myers, Richard H. Ryu, Hannah L. Kowall, Neil W. Song, Eun Joo Hwang, Eun Mi Seo, Hyemyung Lee, Junghee Ryu, Hoon 2024-01-19T14:01:27Z 2024-01-19T14:01:27Z 2021-10-21 2021-09 0301-0082 https://pubs.kist.re.kr/handle/201004/116532 Mitochondrial dysfunction is associated with neuronal damage in Huntington's disease (HD), but the precise mechanism of mitochondria-dependent pathogenesis is not understood yet. Herein, we found that colocalization of XIAP and p53 was prominent in the cytosolic compartments of normal subjects but reduced in HD patients and HD transgenic animal models. Overexpression of mutant Huntingtin (mHTT) reduced XIAP levels and elevated mitochondrial localization of p53 in striatal cells in vitro and in vivo. Interestingly, XIAP interacted directly with the C-terminal domain of p53 and decreased its stability via autophagy. Overexpression of XIAP prevented mitochondrially targeted-p53 (Mito-p53)-induced mitochondrial oxidative stress and striatal cell death, whereas, knockdown of XIAP exacerbated Mito-p53-induced neuronal damage in vitro. In vivo transduction of AAV-shRNA XIAP in the dorsal striatum induced rapid onset of disease and reduced the lifespan of HD transgenic (N171-82Q) mice compared to WT littermate mice. XIAP dysfunction led to ultrastructural changes of the mitochondrial cristae and nucleus morphology in striatal cells. Knockdown of XIAP exacerbated neuropathology and motor dysfunctions in N171-82Q mice. In contrast, XIAP overexpression improved neuropathology and motor behaviors in both AAV-mHTT-transduced mice and N171-82Q mice. Our data provides a molecular and pathological mechanism that deregulation of XIAP triggers mitochondria dysfunction and other neuropathological processes via the neurotoxic effect of p53 in HD. Together, the XIAP-p53 pathway is a novel pathological marker and can be a therapeutic target for improving the symptoms in HD. English PERGAMON-ELSEVIER SCIENCE LTD MITOCHONDRIAL DEATH PROGRAM TRANSGENIC MOUSE MODELS HETEROCHROMATIN CONDENSATION PROMOTES APOPTOSIS MUTANT HUNTINGTIN DIRECT CONVERSION LIGASE ACTIVITY NMR STRUCTURE CYTOCHROME-C CREB-BINDING Dysfunction of X-linked inhibitor of apoptosis protein (XIAP) triggers neuropathological processes via altered p53 activity in Huntington's disease Article 10.1016/j.pneurobio.2021.102110 1 PROGRESS IN NEUROBIOLOGY, v.204 PROGRESS IN NEUROBIOLOGY 204 scie scopus 000684190300004 2-s2.0-85108970277 Neurosciences Neurosciences & Neurology Review MITOCHONDRIAL DEATH PROGRAM TRANSGENIC MOUSE MODELS HETEROCHROMATIN CONDENSATION PROMOTES APOPTOSIS MUTANT HUNTINGTIN DIRECT CONVERSION LIGASE ACTIVITY NMR STRUCTURE CYTOCHROME-C CREB-BINDING XIAP p53 Mitochondria Neurodegeneration Huntington&apos s disease