Stress-granule dynamics in Huntington’s disease

Huntington`s disease (HD) is a late onset neurodegenerative disorder in which a CAG/polyglutamine (polyQ) repeat expansion occurs in the gene encoding the Huntingtin (HTT) protein. This expansion promotes conformational changes in the protein that result in misfolding and aggregation. Work from our lab to characterize the composition of HTT-polyQ aggregates has shown that these aggregates were highly enriched for RNA-binding proteins (RPBs), and in particular, for stress-granule (SG) proteins. Stress granules, composed mainly of RBPs and RNA, form transiently in response to various types of stresses, to temporarily store pre-existing mRNAs and prevent their translation until stress subsides. These findings raise the question whether HD pathogenesis involve impairments in SGs dynamics. To explore that, we performed live-cell imaging, using cell-line models of HD inducibly expressing SG proteins. We compared the behavior of proteins that were sequestered into HTT-polyQ aggregates, namely TIA1, to those which are not, represented by G3BP1. We exposed the cells to oxidative stress, and followed SGs dynamics using advance image analysis tools at a single-cell level. Our preliminary results revealed that HTT-polyQ aggregation is markedly enhanced upon recovery from oxidative stress. Moreover, TIA1 expressing cells demonstrated a significant elevation in aggregates formation compared to cells expressing G3BP1. Additionally, upon stress, cells expressing TIA1 generated significantly less SGs compared to G3BP1 throughout the experiment, a finding which we are further exploring. Although further validation is required, our data suggests that SG-aggregate crosstalk dynamics might be involved in the cellular decline that occurs during HD.