Huntington’s Disease

Expansion of a polyglutamine (polyQ) tract in huntingtin (Htt) protein represents the primary event leading to neuronal degeneration in Huntington’s disease (HD), but the molecular mechanisms mediating mutant Htt (polyQ-Htt) toxicity remain unknown. The selective vulnerability of neurons observed in HD contrasts with the ubiquitous tissue distribution of polyQ-Htt, suggesting that alterations in a cellular process particularly critical for the function and survival of neurons play a central role in HD pathogenesis. Accordingly, several independent reports showed that polyQ-Htt expression results in inhibition of axonal transport, a critical cellular process underlying the maintenance and function of axons and synapses. Conventional kinesin and cytoplasmic dynein (CDyn) are multisubunit motor protein complexes responsible for FAT of material in the anterograde (from the cell body to axons and synapses) and retrograde (from axons and synapses to the cell body), respectively. Recent studies from our group provided a molecular basis underlying the inhibition of anterograde FAT induced by polyQ-Htt. Results from these studies led us to hypothesize that polyQ-Htt-induced inhibition of retrograde FAT involves alterations the functionality and phosphorylation of CDyn. Experiments proposed in this application will help illuminate molecular mechanisms underlying the inhibition of retrograde FAT induced by polyQ-Htt.

Other Grants

Rebekah C. Evans, Ph.D., Georgetown University
In Vivo and Ex Vivo Dissection of Midbrain Neuron Activity During Exercise
Exercise is important for the health of the body and the mind. Exercise promotes learning and reduces symptoms of brain-related diseases such as Parkinson’s disease and Alzheimer’s disease. However, it…
William J. Giardino, Ph.D. Stanford University
Deciphering the Neuropeptide Circuitry of Emotional Arousal in Narcolepsy
This research project aims to investigate the neural mechanisms of a specific type of brain cell called neuropeptide neurons within a region of the brain’s amygdala network called the bed…
Howard Gritton, Ph.D., University of Illinois
Attention Mechanisms Contributing to Auditory Spatial Processing.
Our world is composed of a rich mixture of sounds. We often process sounds including speech in the presence of many other competing auditory stimuli (e.g., voices in a crowded…
Nora Kory, Ph.D., Harvard University
Elucidating the Fates and Functions of Lactate in the Brain
The human brain requires significant energy to function. Despite accounting for only 2% of our body weight, the brain consumes a substantial 20% of the body’s energy, relying on a…