The Huntingtin Transport Complex

A dynamic network of scaffolding molecules, adaptor proteins, and motor proteins work together to orchestrate the movement of proteins, mRNA, and vesicular cargoes. Defects in intracellular transport can often lead to neurodegeneration. Huntingtin (HTT) is a ubiquitously expressed scaffolding protein with a multitude of cellular roles, including regulating the transport of various organelles. HTT is remarkable in its ability to regulate the transport of a wide range of cargoes, including BDNF vesicles, APP vesicles, early endosomes, autophagosomes, lysosomes, and mitochondria. This interaction network allows huntingtin to control microtubule-based transport by kinesin and dynein, as well as actin-based transport by myosin VI. By forming complexes with multiple motor adaptors, huntingtin regulates a variety of cargoes and guides cargoes through the different stages of biosynthesis, signaling, and degradation. Accordingly, pathogenic polyglutamine expansions seen in Huntington's Disease (HD) dysregulate huntingtin transport complexes, resulting in defects in transport and neurodegeneration.