Huntingtin protein–protein interactions: From biology to therapeutic targets

Huntingtin (HTT) is a largely alpha-helical protein that is ubiquitously expressed in many tissues and cell types. This protein has been extensively studied because an abnormally expanded polyglutamine (polyQ) stretch, located at its N-terminus, leads to Huntington's disease (HD), an inherited, late-onset neurodegenerative disease with severe motor, cognitive and psychiatric symptoms. To elucidate HTT function and its role in disease, numerous protein–protein interaction (PPI) mapping studies have been performed, which have revealed ∼3400 HTT candidate interaction partners. Here, we provide an overview of HTT interaction mapping efforts and an integrated computational analysis of HTT interacting proteins (HIPs) based on currently available literature. We discuss and apply various PPI selection criteria as well as highlight potential hub interacting proteins and complexes for defining “high-confidence” HIPs for further functional characterization and potential therapeutic efforts.