SUMOylation Prevents Huntingtin Fibrillization and Localization onto Lipid Membranes

Abstract

Huntington's disease (HD), a genetic neurodegenerative disease, is caused by an expanded polyglutamine (polyQ) domain in the first exon of the huntingtin protein (htt). PolyQ expansion destabilizes protein structure, resulting in aggregation into a variety of oligomers, protofibrils, and fibrils. Beyond the polyQ domain, adjacent protein sequences influence the aggregation process. Specifically, the first 17 N-terminal amino acids (Nt17) directly preceding the polyQ domain promote the formation of α-helix-rich oligomers that represent intermediate species associated with fibrillization. Due to its propensity to form an amphipathic α-helix, Nt17 also facilitates lipid binding. Three lysine residues (K6, K9, and K15) within Nt17 can be SUMOylated, which modifies htt's accumulation and toxicity within cells in a variety of HD models. The impact of SUMOylation on htt aggregation and direct interaction with lipid membranes was investigated. SUMOylation of htt-exon1 inhibited fibril formation while promoting larger, amorphous aggregate species. These amorphous aggregates were SDS soluble but nonetheless exhibited levels of β-sheet structure similar to that of htt-exon1 fibrils. In addition, SUMOylation prevented htt binding, aggregation, and accumulation on model lipid bilayers comprised of total brain lipid extract. Collectively, these observations demonstrate that SUMOylation promotes a distinct htt aggregation pathway that may affect htt toxicity.

Keywords: Amyloid; Huntington’s disease; amphipathic α-helix; fibrils; oligomers; polyglutamine.