{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T19:09:00Z","timestamp":1791486540907,"version":"4.3.4"},"posted":{"date-parts":[[2023,10,16]]},"group-title":"Neurology","reference-count":27,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,10,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>The PINK1-PRKN pathway mediates a critical quality control to maintain mitochondrial health and function. Together the kinase-ligase pair identifies and decorate damaged mitochondria with phosphorylated ubiquitin (p-S65-Ub). This selective label serves as the mitophagy tag and facilitates their degradation via autophagy-lysosome system. While complete loss of PINK1 or PRKN function causes early-onset Parkinson disease, much broader mitophagy impairments are emerging across neurodegenerative disorders. We previously found age- and disease-dependent accumulation of p-S65-Ub signal in the hippocampus of autopsy brains with Lewy body disease (LBD). However, the contribution of genetic variation to mitochondrial damage and p-S65-Ub levels remains unknown in LBD cases. To identify novel regulators of PINK1-PRKN mitophagy in LBD, we performed an unbiased genome-wide association study of hippocampal p-S65-Ub level with 1,012 autopsy confirmed LBD samples. Using an established, mostly automated workflow, hippocampal sections were immunostained for p-S65-Ub, scanned, and quantified with unbiased algorithms. Functional validation of the significant hit was performed in animal model and human induced pluripotent stem cells (hiPSCs).<\/jats:p>\n                <jats:p>\n                  We identified a strong association with p-S65-Ub for\n                  <jats:italic>APOE4<\/jats:italic>\n                  (rs429358;\n                  <jats:italic>\u03b2<\/jats:italic>\n                  : 0.50, 95% CI: 0.41 to 0.69;\n                  <jats:italic>p<\/jats:italic>\n                  =8.67x10\n                  <jats:sup>-25<\/jats:sup>\n                  ) and a genome-wide significant association for\n                  <jats:italic>ZMIZ1<\/jats:italic>\n                  (rs6480922;\n                  <jats:italic>\u03b2<\/jats:italic>\n                  : -0.33, 95% CI: -0.45 to -0.22;\n                  <jats:italic>p<\/jats:italic>\n                  =1.42x10\n                  <jats:sup>-8<\/jats:sup>\n                  ). The increased p-S65-Ub levels in\n                  <jats:italic>APOE4<\/jats:italic>\n                  -carrier may be mediated by both co-pathology-dependent and -independent mechanisms, which was confirmed in Apoe-targeted replacement mice and hiPSC-derived astrocytes. Intriguingly,\n                  <jats:italic>ZMIZ1<\/jats:italic>\n                  rs6480922 also significantly associated with increased brain weight and reduced neuropathological burden indicating a potential role as a resilience factor. Our findings nominate novel mitophagy regulators in LBD brain (\n                  <jats:italic>ZMIZ1<\/jats:italic>\n                  locus) and highlight a strong association of\n                  <jats:italic>APOE4<\/jats:italic>\n                  with mitophagy alteration. With\n                  <jats:italic>APOE4<\/jats:italic>\n                  being the strongest known risk factor for clinical Alzheimer\u2019s disease and dementia with Lewy bodies, our findings suggest a common mechanistic link underscoring the importance of mitochondrial quality control.\n                <\/jats:p>","DOI":"10.1101\/2023.10.16.23297100","type":"posted-content","created":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T23:15:17Z","timestamp":1697498117000},"source":"Crossref","is-referenced-by-count":7,"title":["Genome-wide association study identifies\n                  <i>APOE<\/i>\n                  and\n                  <i>ZMIZ1<\/i>\n                  variants as mitophagy modifiers in Lewy body disease"],"prefix":"10.64898","author":[{"given":"Xu","family":"Hou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael G.","family":"Heckman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabienne C.","family":"Fiesel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunsuke","family":"Koga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra I.","family":"Soto-Beasley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens O.","family":"Watzlawik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca R.","family":"Valentino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick W.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Launia J.","family":"White","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary S.","family":"Quicksall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph S.","family":"Reddy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose","family":"Bras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Guerreiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guojun","family":"Bu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis W.","family":"Dickson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Owen A.","family":"Ross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfdieter","family":"Springer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2023101912200534000_2023.10.16.23297100v1.1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-021-00501-z"},{"key":"2023101912200534000_2023.10.16.23297100v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(18)30499-X"},{"key":"2023101912200534000_2023.10.16.23297100v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/s1474-4422(17)30400-3"},{"key":"2023101912200534000_2023.10.16.23297100v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(19)30320-5"},{"key":"2023101912200534000_2023.10.16.23297100v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00785-3"},{"key":"2023101912200534000_2023.10.16.23297100v1.6","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-021-02266-7"},{"key":"2023101912200534000_2023.10.16.23297100v1.7","doi-asserted-by":"publisher","DOI":"10.3233\/JPD-160989"},{"key":"2023101912200534000_2023.10.16.23297100v1.8","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2018.1461294"},{"key":"2023101912200534000_2023.10.16.23297100v1.9","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12198"},{"key":"2023101912200534000_2023.10.16.23297100v1.10","doi-asserted-by":"publisher","DOI":"10.1111\/bpa.13175"},{"key":"2023101912200534000_2023.10.16.23297100v1.11","doi-asserted-by":"publisher","DOI":"10.1101\/gr.094052.109"},{"key":"2023101912200534000_2023.10.16.23297100v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3656"},{"key":"2023101912200534000_2023.10.16.23297100v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/ng1706"},{"key":"2023101912200534000_2023.10.16.23297100v1.14","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.29.17972"},{"key":"2023101912200534000_2023.10.16.23297100v1.15","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2020.1834712"},{"key":"2023101912200534000_2023.10.16.23297100v1.16","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx155"},{"key":"2023101912200534000_2023.10.16.23297100v1.17","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201540514"},{"key":"2023101912200534000_2023.10.16.23297100v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-019-0228-7"},{"key":"2023101912200534000_2023.10.16.23297100v1.19","doi-asserted-by":"publisher","DOI":"10.1126\/science.8346443"},{"key":"2023101912200534000_2023.10.16.23297100v1.20","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000006212"},{"key":"2023101912200534000_2023.10.16.23297100v1.21","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24010778"},{"key":"2023101912200534000_2023.10.16.23297100v1.22","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-019-0323-7"},{"key":"2023101912200534000_2023.10.16.23297100v1.23","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-018-0892-4"},{"key":"2023101912200534000_2023.10.16.23297100v1.24","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-022-02216-0"},{"key":"2023101912200534000_2023.10.16.23297100v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2019.11.014"},{"key":"2023101912200534000_2023.10.16.23297100v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2021.119900"},{"key":"2023101912200534000_2023.10.16.23297100v1.27","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abp8869"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2023.10.16.23297100","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:43:14Z","timestamp":1768506194000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2023.10.16.23297100"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,16]]},"references-count":27,"URL":"https:\/\/doi.org\/10.1101\/2023.10.16.23297100","relation":{},"subject":[],"published":{"date-parts":[[2023,10,16]]},"subtype":"preprint"}}