Venue: IECB
Patrick van der Wel
Zernike Institute for Advanced Materials, University of Groningen, The Netherlands
https://vanderwellab.org/
Title
Structural and mechanistic studies of protein aggregation in Huntington’s disease.
Abstract
Huntington’s disease (HD) is part of a class of neurodegenerative diseases characterized by the aggregation of misfolded proteins. In HD, aggregation involves fragments of mutated huntingtin (HTT) proteins, which are characterized by an expanded polyglutamine (polyQ) segment. Since its discovery in the 1990s, the HD field has been trying to understand the life cycle of the mutant protein, how it aggregates, and how HTT aggregates contribute to HD pathology. One of the open challenges has been the development of a molecular understanding of the HTT protein’s (mis)behavior – information essential for understanding HD disease processes, developing diagnostics, and overcoming the lack of HD treatments. Over the past fifteen years, my group has been dissecting the structure of polyQ-expanded HTT-based aggregates, combining advanced solid-state NMR spectroscopy with biochemical, biophysical and mechanistic studies. I will discuss our recently reported atomic-level description of HTT aggregates, exemplifying how integrative approaches can succeed when cryo-EM proves diZicult. I will describe our mechanistic and structural insights on aggregation inhibitors that modulate the toxicity of HTT aggregates, and our ongoing studies of how inhibitors, ligands, and antibodies can selectively recognize the misfolded HTT protein. Finally, I will discuss how structural studies are essential for understanding the cellular interactions of these intracellular protein aggregates, including their argeting by protein quality control mechanisms.