{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T05:44:48Z","timestamp":1792734288173,"version":"4.5.0"},"reference-count":73,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T00:00:00Z","timestamp":1658188800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NS110943"],"award-info":[{"award-number":["NS110943"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AG057509"],"award-info":[{"award-number":["AG057509"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005725","name":"CHDI Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>Perturbation of huntingtin (HTT)\u2019s physiological function is one postulated pathogenic factor in Huntington\u2019s disease (HD). However, little is known how HTT is regulated <jats:italic>in vivo<\/jats:italic>. In a proteomic study, we isolated a novel ~40kDa protein as a strong binding partner of <jats:italic>Drosophila<\/jats:italic> HTT and demonstrated it was the functional ortholog of HAP40, an HTT associated protein shown recently to modulate HTT\u2019s conformation but with unclear physiological and pathologic roles. We showed that in both flies and human cells, HAP40 maintained conserved physical and functional interactions with HTT. Additionally, loss of HAP40 resulted in similar phenotypes as HTT knockout. More strikingly, HAP40 strongly affected HTT\u2019s stability, as depletion of HAP40 significantly reduced the levels of endogenous HTT protein while HAP40 overexpression markedly extended its half-life. Conversely, in the absence of HTT, the majority of HAP40 protein were degraded, likely through the proteasome. Further, the affinity between HTT and HAP40 was not significantly affected by polyglutamine expansion in HTT, and contrary to an early report, there were no abnormal accumulations of endogenous HAP40 protein in HD cells from mouse HD models or human patients. Lastly, when tested in <jats:italic>Drosophila<\/jats:italic> models of HD, HAP40 partially modulated the neurodegeneration induced by full-length mutant HTT while showed no apparent effect on the toxicity of mutant HTT exon 1 fragment. Together, our study uncovers a conserved mechanism governing the stability and <jats:italic>in vivo<\/jats:italic> functions of HTT and demonstrates that HAP40 is a central and positive regulator of endogenous HTT. Further, our results support that mutant HTT is toxic regardless of the presence of its partner HAP40, and implicate HAP40 as a potential modulator of HD pathogenesis through its multiplex effect on HTT\u2019s function, stability and the potency of mutant HTT\u2019s toxicity.<\/jats:p>","DOI":"10.1371\/journal.pgen.1010302","type":"journal-article","created":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T17:23:37Z","timestamp":1658251417000},"page":"e1010302","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":19,"title":["HAP40 is a conserved central regulator of Huntingtin and a potential modulator of Huntington\u2019s disease 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