Dysfunction of X-linked inhibitor of apoptosis protein (XIAP) triggers neuropathological processes via altered p53 activity in Huntington's disease
- 주제(키워드) XIAP , p53 , Mitochondria , Neurodegeneration , Huntington's disease
- 주제(기타) Neurosciences
- 설명문(일반) [Hyeon, Seung Jae; Yoo, Junsang; Kim, Su-Hyun; Hwang, Yu Jin; Shim, Hyun Soo; Kim, Yunha; Kim, Key-Sun; Ryu, Hoon] Korea Inst Sci & Technol, Brain Sci Inst, Ctr Neurosci, Seoul 02792, South Korea; [Hyeon, Seung Jae; Seo, Hyemyung] Hanyang Univ, Ctr Bionano Intelligence Educ & Res, Dept Mol & Life Sci, Ansan 15588, South Korea; [Park, Jinyoung] Korea Inst Sci & Technol, Mol Recognit Res Ctr, Seoul 02792, South Korea; [Kim, Seung-Chan; Hwang, Eun Mi] Korea Inst Sci & Technol, Brain Sci Inst, Ctr Funct Connect, Seoul 02792, South Korea; [Liu, Tian] Univ S Florida, Coll Med, USF Hlth Byrd Alzheimers Inst, Tampa, FL 33613 USA; [Liu, Tian] Univ S Florida, Coll Med, Dept Mol Med, Tampa, FL 33613 USA; [Cho, Yakdol; Woo, Jiwan; Kim, Key-Sun] Korea Inst Sci & Technol, KIST Res Anim Resource Ctr, Seoul 02792, South Korea; [Myers, Richard H.] Boston Univ, Sch Med, Genome Sci Inst, Boston, MA 02118 USA; [Myers, Richard H.; Ryu, Hannah L.; Kowall, Neil W.; Lee, Junghee; Ryu, Hoon] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA; [Ryu, Hannah L.; Kowall, Neil W.; Lee, Junghee; Ryu, Hoon] Boston Univ, Sch Med, Alzheimers Dis Ctr, Boston, MA 02118 USA; [Kowall, Neil W.; Lee, Junghee] VA Boston Healthcare Syst, Boston, MA 02130 USA; [Song, Eun Joo] Ewha Womans Univ, Coll Pharm, Grad Sch Pharmaceut Sci, Seoul 03760, South Korea; [Yoo, Junsang] Stem Cell & Cell Reprogramming Res Ctr, Sinsadong 559-8, Seoul 06037, South Korea
- 등재 SCIE, SCOPUS
- 발행기관 PERGAMON-ELSEVIER SCIENCE LTD
- 발행년도 2021
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000183276
- 본문언어 영어
- Published As http://dx.doi.org/10.1016/j.pneurobio.2021.102110
초록/요약
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.
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