HAP40 is a conserved central regulator of Huntingtin and a potential modulator of Huntington’s disease pathogenesis
| Autor: | Shiyu Xu, Gang Li, Xin Ye, Dongsheng Chen, Zhihua Chen, Zhen Xu, Moretti Daniele, Sara Tambone, Alessandra Ceccacci, Licia Tomei, Lili Ye, Yue Yu, Amanda Solbach, Stephen M. Farmer, Erin Furr Stimming, George McAllister, Deanna M. Marchionini, Sheng Zhang |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | PLoS Genetics, Vol 18, Iss 7 (2022) |
| Druh dokumentu: | article |
| ISSN: | 1553-7390 1553-7404 |
| Popis: | Perturbation of huntingtin (HTT)’s physiological function is one postulated pathogenic factor in Huntington’s disease (HD). However, little is known how HTT is regulated in vivo. In a proteomic study, we isolated a novel ~40kDa protein as a strong binding partner of Drosophila HTT and demonstrated it was the functional ortholog of HAP40, an HTT associated protein shown recently to modulate HTT’s 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’s 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 Drosophila 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 in vivo 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’s function, stability and the potency of mutant HTT’s toxicity. Author summary Abnormal polyglutamine expansion in huntingtin (HTT) protein causes neurodegenerative Huntington’s disease (HD). Given the complex and still unclear pathogenic mechanisms underlying HD, there is great interest in targeting HTT as a therapeutic strategy against HD. Accordingly, it is important to understand how HTT is normally regulated. In a proteomic study in Drosophila, we isolated a novel protein as a strong binding partner of fly HTT homolog and demonstrated that it was the functional counterpart of mammalian HAP40, a protein known to modulate HTT’s conformation but with unclear physiological and pathologic roles. We found that the physical and functional interactions of HTT with HAP40 were conserved from flies to human cells, and HAP40 was essential for HTT’s normal functions and protein stability, while in the absence of HTT, HAP40 was quickly cleared through the proteasome. Further, polyglutamine expansion in HTT protein did not affect its affinity for HAP40 or cause abnormal accumulation of HAP40 in HD cells. Lastly, we observed that HAP40 could modulate HD-associated neurodegeneration in fly models that expressed full-length mutant HTT. Together, our study demonstrates that HAP40 is a highly conserved and essential regulator of HTT and a potential candidate for achieving specific HTT-lowering in HD cells. |
| Databáze: | Directory of Open Access Journals |
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