To better understand the role of HAP40 and it's relationship with huntingtin in the pathogenesis of Huntington's disease (HD).

HD is caused by an abnormal glutamine expansion in the huntingtin (HTT) protein. As a large scaffold protein, HTT is implicated in a  list of cellular processes. Little is known how these diverse functions are integrated and how HTT itself is regulated. 

Converging evidence supports HAP40 as a central regulator of HTT. HAP40 was originally isolated from rat and mouse brains as the “most significantly correlated” partner of endogenous HTT protein, and binds HTT in a stochastic 1:1 molar ratio.  A ~10-fold increase of the levels of endogenous HAP40 were observed in samples from HD patients as compared to healthy controls. There is no reported functional evaluation of HAP40 in any physiological setting.

Our results demonstrate that HAP40 is an essential regulator of HTT’s physiological functions and an effective modifier of HD pathogenesis. Given the complex pathogenic mechanisms underlying HD, a clear understanding of central HTT regulators such as HAP40 is essential for “HTT-lowering” and other strategies against HD.