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Dysfunction of X-linked inhibitor of apoptosis protein (XIAP) triggers neuropathological processes via altered p53 activity in Huntington's disease

Title
Dysfunction of X-linked inhibitor of apoptosis protein (XIAP) triggers neuropathological processes via altered p53 activity in Huntington's disease
Authors
Hyeon, Seung JaePark, JinyoungYoo, JunsangKim, Su-HyunHwang, Yu JinKim, Seung-ChanLiu, TianShim, Hyun SooKim, YunhaCho, YakdolWoo, JiwanKim, Key-SunMyers, Richard H.Ryu, Hannah L.Kowall, Neil W.Song, Eun JooHwang, Eun MiSeo, HyemyungLee, JungheeRyu, Hoon
Ewha Authors
송은주
SCOPUS Author ID
송은주scopus
Issue Date
2021
Journal Title
PROGRESS IN NEUROBIOLOGY
ISSN
0301-0082JCR Link

1873-5118JCR Link
Citation
PROGRESS IN NEUROBIOLOGY vol. 204
Keywords
XIAPp53MitochondriaNeurodegenerationHuntington's disease
Publisher
PERGAMON-ELSEVIER SCIENCE LTD
Indexed
SCIE; SCOPUS WOS
Document Type
Review
Abstract
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.
DOI
10.1016/j.pneurobio.2021.102110
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약학대학 > 약학과 > Journal papers
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