Characterization of the structural properties of polyQ proteins accounting for the early neuropathy

Abstract

Polyglutamine (polyQ) diseases are caused by expansion of glutamine (Q) repeats within the associated protein that induces formation of the intracellular protein aggregates. Collected evidence to date suggests that strong tendency of these mutated proteins toward forming oligo-mers and/or aggregates together with their numerous targets may be the primary cause of the tox-icity causing neuropathy. However, it remains largely unclear what characteristics of the pathogenic polyQ proteins cause these inclusion bodies and how these properties contribute to the various aspects of the disease pathogenesis. Here, we studied what properties of the pathogenic polyQ proteins are primarily associated with the specific early neuropathy, the distal dendrite defects. Different types of structural variants of polyQ proteins had been generated, and only structural variants possessing coiled coil propensity were able to induce the dendrite defects, accompanied by their preferred localization in the nucleus. Given that total mRNA level was decreased by expression of the pathogenic SCA3 accumulated within the nucleus, the observed early neuropathy appeared to be closely associated with the changes in the nuclear transcriptome. Furthermore, we demonstrated that Q continuity within the associated protein is also required for the dendrite abnormalities. In addition, coiled coil property of toxic SCA3 proteins seemed to be critical for interactions with their potential targets as well as their self-aggregation. Taken together, both coiled coil property and Q continuity may be the key contributors necessary for inducing distal dendrite defects caused by pathogenic SCA3. ⓒ 2015 DGIST