Xu Hou, Michael G. Heckman, Fabienne C. Fiesel, Shunsuke Koga, Alexandra I. Soto-Beasley, Jens O. Watzlawik, Jing Zhao, Rebecca R. Valentino, Patrick W. Johnson, Launia J. White, Zachary S. Quicksall, Joseph S. Reddy, Jose Bras, Rita Guerreiro, Na Zhao, Guojun Bu, Dennis W. Dickson, Owen A. Ross, Wolfdieter Springer
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Despite the widespread deposition of p-S65-Ub in aged and diseased human brain, the genetic contribution to its accumulation remains unclear.</p>\n </section>\n \n <section>\n \n <h3> METHODS</h3>\n \n <p>To identify novel mitophagy regulators, we performed a genome-wide association study using p-S65-Ub level as a quantitative trait in 1012 autopsy-confirmed Lewy body disease (LBD) samples.</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p>We identified a significant genome-wide association with p-S65-Ub for rs429358 (<i>apolipoprotein E ε4</i> [<i>APOE</i>4]) and a suggestive association for rs6480922 (<i>ZMIZ1</i>). <i>APOE</i>4 was associated with higher p-S65-Ub levels and greater neuropathological burden. Functional validation in mouse and human induced pluripotent stem cell (iPSC) models confirmed <i>APOE</i>4-mediated mitophagy alterations. Intriguingly, <i>ZMIZ1</i> rs6480922 was associated with lower p-S65-Ub levels, reduced neuropathological load, and increased brain weight, indicating a potential protective role.</p>\n </section>\n \n <section>\n \n <h3> DISCUSSION</h3>\n \n <p>Our findings underscore the importance of mitochondrial quality control in LBD pathogenesis and nominate regulators that may contribute to disease risk or resilience.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li>p-S65-Ub levels were used as a quantitative marker of mitochondrial damage.</li>\n \n <li>A GWAS identified two genetic variants that modify mitophagy in LBD autopsy brain.</li>\n \n <li><i>APOE</i>4 was associated with increased p-S65-Ub accumulation and neuropathology.</li>\n \n <li><i>APOE</i>4 altered mitophagy via pathology-dependent and pathology-independent mechanisms.</li>\n \n <li><i>ZMIZ1</i> was linked to reduced p-S65-Ub and neuropathology indicative of protection.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 4","pages":""},"PeriodicalIF":13.0000,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70198","citationCount":"0","resultStr":"{\"title\":\"Genome-wide association analysis identifies APOE as a mitophagy modifier in Lewy body disease\",\"authors\":\"Xu Hou, Michael G. 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Genome-wide association analysis identifies APOE as a mitophagy modifier in Lewy body disease
INTRODUCTION
Phosphorylated ubiquitin (p-S65-Ub) is generated during PINK1-PRKN mitophagy as a specific marker of mitochondrial damage. Despite the widespread deposition of p-S65-Ub in aged and diseased human brain, the genetic contribution to its accumulation remains unclear.
METHODS
To identify novel mitophagy regulators, we performed a genome-wide association study using p-S65-Ub level as a quantitative trait in 1012 autopsy-confirmed Lewy body disease (LBD) samples.
RESULTS
We identified a significant genome-wide association with p-S65-Ub for rs429358 (apolipoprotein E ε4 [APOE4]) and a suggestive association for rs6480922 (ZMIZ1). APOE4 was associated with higher p-S65-Ub levels and greater neuropathological burden. Functional validation in mouse and human induced pluripotent stem cell (iPSC) models confirmed APOE4-mediated mitophagy alterations. Intriguingly, ZMIZ1 rs6480922 was associated with lower p-S65-Ub levels, reduced neuropathological load, and increased brain weight, indicating a potential protective role.
DISCUSSION
Our findings underscore the importance of mitochondrial quality control in LBD pathogenesis and nominate regulators that may contribute to disease risk or resilience.
Highlights
p-S65-Ub levels were used as a quantitative marker of mitochondrial damage.
A GWAS identified two genetic variants that modify mitophagy in LBD autopsy brain.
APOE4 was associated with increased p-S65-Ub accumulation and neuropathology.
APOE4 altered mitophagy via pathology-dependent and pathology-independent mechanisms.
ZMIZ1 was linked to reduced p-S65-Ub and neuropathology indicative of protection.
期刊介绍：
Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.
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