Protein aggregation in Huntington's disease

TL;DR

This paper discusses the mechanisms of protein aggregation in Huntington's disease, focusing on hydrogen bonds and covalent bonds, and highlights the importance of understanding these bonds for developing therapies.

Contribution

It reviews the current understanding of aggregation mechanisms in Huntington's disease and emphasizes the need to identify the stabilizing bonds in patient brains.

Findings

Aggregates in cell models are mainly stabilized by hydrogen bonds.

Covalent bonds via transglutaminase may also contribute to aggregation.

The nature of bonds in patient brain aggregates remains unknown.

Abstract

The presence of an expanded polyglutamine produces a toxic gain of function in huntingtin. Protein aggregation resulting from this gain of function is likely to be the cause of neuronal death. Two main mechanisms of aggregation have been proposed: hydrogen bonding by polar-zipper formation and covalent bonding by transglutaminase-catalyzed cross-linking. In cell culture models of Huntington's disease, aggregates are mostly stabilized by hydrogen bonds, but covalent bonds are also likely to occur. Nothing is known about the nature of the bonds that stabilize the aggregates in the brain of patients with Huntington's disease. It seems that the nature of the bond stabilizing the aggregates is one of the most important questions, as the answer would condition the therapeutic approach to Huntington's disease.