Project 467150

Huntingtin (HTT) is a multifunctional and ubiquitous scaffolding protein playing an essential role in intracellular transport through the control of motor proteins, kinesin and dynein. HTT mediated bidirectional transport by kinesins and dynein is essential to a variety of cellular processes including transcription, nucleocytoplasmic shuttling, synaptic function, and apoptosis. The misregulation of bidirectional transport caused by mutant huntingtin (mHTT) in neurons leads to defects in intracellular processes. In Huntingtins Disease (HD), an expanded CAG repeat in the huntingtin gene encodes an abnormally long polyglutamine repeat resulting in the production of mHTT. Huntingtin mutants accumulate and aggregate in neurons causing defects in intracellular transport that often amount to neurodegeneration. HD is a fatal disorder characterized by vast neurodegeneration causing a gradual loss of motor control and cognitive ability. Altered intracellular transport has been observed in cellular and animal models of Huntingtons Disease, however little is known about the effect of mHTT on interactions between motor proteins, vesicular cargoes, and microtubules. We will employ high-resolution imaging techniques and reconstruct organelle motility in vitro to identify mechanisms by which HTT regulates intracellular transport. We will determine if mHTT disrupts transport through altering the recruitment and activity of motor proteins and adapters to vesicular cargoes or by forming aggregates that act as obstacles to transport. Our investigations will uncover the regulatory mechanisms that govern intracellular transport, determine how defects result in neurodegeneration, and identify potential therapeutic targets.