Year: 2013
Type: article
Abstract: Protein misfolding as a result of polyglutamine (polyQ) repeat expansion plays a crucial role in the development a class of neurodegenerative disorders. These disorders are characterized by expansions in unique proteins, but share one common factor: polyQ repeat expansions beyond a pathological threshold, usually near 35 Glns. PolyQ containing peptides and proteins aggregate into amyloid-like fibrils, in both disease states and in vitro. While recent studies of simple polyQ aggregation have led to the development of a mechanism describing the fibril formation pathway, the kinetic and thermodynamic roles of even small modifications to the amino acid sequence are unclear. The goal of this work was to gain more specific information regarding the biophysical roles of terminal charge and Gln repeat length in the aggregation mechanism of simple polyQ peptides. We found that increases in both repeat length and attraction between terminal flanking sequences led to enhancements in fibril stability and spontaneous aggregation ability. In general, mutations in polyQ sequences that enhance their ability to assume a β-hairpin structure (the proposed building block of polyQ fibrils), and to associate with each other facilitate fibrillization through a nucleated polymerization pathway with a monomeric nucleus. The data discussed here have made significant contributions to our understanding of the basic aggregation properties of polyQ peptides, and have implications that can be directly translated to polyQ disease pathogenesis.
Author: Elizabeth Landrum
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2134843158