Implications Of Cis Interactions Between Expanded Polyglutamine and the Proline Rich C-Terminal Domain of Huntingtin Exon 1 For the Loss- Versus Gain-Of-Function Models of Huntington's Disease

Abstract

At least nine neurodegenerative disorders, including Huntington's disease (HD), have been associated with expanded polyglutamine (polyQ) tracts. Proteolytic products of these proteins form neuronal intranuclear inclusions. There is growing interest in the role of naturally occurring flanking sequences and persistent controversy regarding their role as gatekeepers against or enhancers of polyQ aggregation. In particular, previous studies have shown that the 17-residue N-terminal segment (N17) of huntingtin (htt) exon 1 acts as gatekeepers, although controversy lingers with regards to this finding. Here, we focus on the interactions in cis between polyQ and the proline rich C-terminal domain (C38) of htt exon 1. This domain possesses two polyproline stretches (polyP) that appear to interact with profilin, which inhibits htt aggregation in cell culture studies.Through the use of atomistic Monte Carlo simulations utilizing the ABSINTH implicit solvation model, we show evidence for long-range interactions between polyQ tracts and both polyP regions. The polyQ segments promote the formation of cis peptide bonds within the polyP segment directly C-terminal to polyQ. This in turn will have important changes to the heterotypic interactions of htt through its polyP regions. A detailed comparative analysis of the monomer ensembles of N17-polyQ, polyQ-C38 and N17-polyQ-C38 constructs will be presented and the implications of our findings for loss- versus gain-of-function models for the onset and progression of disease will be discussed.This work was supported by grant 5R01NS056114 from the National Institutes of Health