Huntington’s Disease

Effects of Mutant Huntingtin on Cytoplasmic Dynein Phosphorylation and Function
2011 Seed Grant
Gerardo Morfini, Ph.D.
Department of Anatomy and Cell Biology
University of Illinois at Chicago

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.

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