HAP40 is a conserved central regulator of Huntingtin and a specific modulator of mutant Huntingtin toxicity

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 a proteomic study, we isolated a novel ∼40kDa protein as a strong binding partner of 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, loss of HAP40 resulted in similar phenotypes as HTT knockout, including animal viability and autophagy, and more strikingly, HAP40 depletion significantly reduced the levels of endogenous HTT, while HAP40 was mostly degraded via the proteasome in the absence of HTT. Interestingly, polyglutamine expansion in HTT did not affect its affinity for HAP40. However, HAP40 modulated HD pathogenesis in model by regulating the overall protein levels and the toxicity of full-length mutant HTT. Together, our study uncovers a conserved mechanism governing the stability and functions of HTT, and demonstrates that HAP40 is a central and positive regulator of HTT, a potential modulator of HD pathogenesis and a promising candidate for “HTT-lowering” strategy against HD.