Congratulations to lab alum Dr. Hsiang-Kai Lin, graduate student Jennifer Boatz, and our collaborators locally and abroad! Our new publication describing the structure and properties of mutant huntingtin exon 1 fibrils has been published in the journal Nature Communications. The paper describes our ongoing studies of the mutant protein behind the devastating neurodegeneration in Huntington’s Disease. Biochemical and structural experiments show that mutant huntingtin exon 1 forms at least two types of neurotoxic aggregates with different internal structures. Through the use of solid-state NMR spectroscopy and electron microscopy we look at the molecular details of these structural differences. Various other disease-related amyloid proteins have a similar tendency to form different types of aggregates (i.e. amyloid polymorphism), usually mediated by changes in the β-sheets of the amyloid assemblies they form. Surprisingly, in these huntingtin aggregates the polymorphism is due primarily to supramolecular change in the interactions among exposed and dynamic non-amyloid “flanking” domains. Importantly, it is these flanking domains that are targeted by protective chaperones, but they also mediate interactions with cellular membranes that may contribute to the toxic mechanism.
Publication info: Lin H-K, Boatz JC, Krabbendam IE, et al (2017) Fibril polymorphism affects immobilized non-amyloid flanking domains of huntingtin exon1 rather than its polyglutamine core. Nat Commun 8:15462.