The misfolding and aggregation of huntingtin is one of the hallmarks of Huntington’s disease, but the molecular mechanisms of misfolding remain poorly understood.  Such knowledge would be useful for the design of biomarkers and therapeutics that detect and/or prevent the formation of toxic, misfolded species. Using a combination of biochemical and biophysical methods, we isolated different misfolding intermediates and characterized them structurally.  We find that huntingtin misfolding is a stepwise process, in which early helical intermediates precede the formation of β-sheet containing oligomers and fibrils of various structures. Having isolated the different misfolded species, it also became possible to obtain conformationally specific small molecules, peptides and antibodies. In addition to being potential biomarkers for the various misfolded species, some of these binders also potently inhibited misfolding. Among the most potent misfolding inhibitors were peptides specific for fibrils. The peptides appear to protect from seeding by blocking seeding-competent surfaces. The biological properties of these binders are currently tested in cultured cells and animal model systems of Huntington’s disease.   <br/>

Targeting huntingtin misfolding using conformationally specific binders: Implications for therapy and biomarker development in Huntington’s disease

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.