한빛사논문
Seung Jae Hyeona,b, Jinyoung Parkc, Junsang Yooa,1, Su-Hyun Kima, Yu Jin Hwanga, Seung-Chan Kimd, Tian Liue, Hyun Soo Shima, Yunha Kima, Yakdol Chof, Jiwan Woof, Key-Sun Kima,f, Richard H. Myersg, Hannah L. Ryuh, Neil W. Kowallh,i, Eun Joo Songj, Eun Mi Hwangd, Hyemyung Seob,*, Junghee Leeh,i,*, Hoon Ryua,h,*
aCenter for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, South Korea
bDepartment of Molecular & Life Sciences, Center for Bionano Intelligence Education and Research, Hanyang University, Ansan 15588, South Korea
cMolecular Recognition Research Center, Korea Institute of Science and Technology, Seoul 02792, South Korea
dCenter for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, South Korea
eUSF Health Byrd Alzheimer’s Institute and Department of Molecular Medicine, University of South Florida College of Medicine, Tampa, FL 33613, USA
fKIST Research Animal Resource Center, Korea Institute of Science and Technology, Seoul 02792, South Korea
gBoston University Genome Science Institute and Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA
hBoston University Alzheimer’s Disease Center and Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA
iVA Boston Healthcare System, Boston, MA 02130, USA
jGraduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760, South Korea
1Current address: Stem Cell & Cell Reprogramming Research Center, Sinsadong 559-8, Gangnam gu, Seoul 06037, South Korea.
*Corresponding authors
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.
Keywords : Huntington’s disease, XIAP, p53, Mitochondria, Neurodegeneration
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