Ronald Wetzel, University of Pittsburgh School of Medicine
How to stop Huntington’s Disease-associated polyglutamine amyloid accumulation … before it starts
Host: Pr. Legleiter
Professor, Department of Structural Biology, University of Pittsburgh School of Medicine; Member, Pittsburgh Institute for Neurodegenerative Diseases
Huntington’s disease (HD) is a genetic neurodegenerative malady associated with
the expansion of a CAG encoding-, in-frame polyglutamine (polyQ) repeat sequence
in the huntingtin protein. In 1997, demonstration of the strong repeat
length dependence of polyQ aggregation, plus the discovery of polyQ-containing
huntingtin aggregates in HD neurons, suggested a causative role for polyQ aggregation.
My lab has been investigating the mechanism by which httNT, a short peptide segment
flanking the N-terminus of the polyQ tract in huntingtin, greatly stimulates
amyloid formation by the neighboring polyQ. I will begin the talk with
a brief introduction to Huntington’s Disease, the data supporting a role for
protein aggregation, and a summary of my lab’s previous work characterizing the
nature of the httNT effect. This will be followed by a short description of the
general physical and cellular factors that may influence amyloid formation.
I will conclude by presenting an analysis of Alanine scanning mutational data
that reveals in exquisite structural detail the mechanism by which httNT initiates
polyQ aggregation. The results suggest exciting new opportunities for discovery
of small molecule HD therapeutics.