Cell-Type Specific Translational Profiling in Huntington\u27s Disease Mouse Models

Medium spiny neurons (MSNs) are among the most vulnerable cell populations in Huntington’s Disease (HD). Within this population, striatopallidal MSNs are more vulnerable than striatonigral MSNs, which may explain the typical progression in HD of chorea to hypokinesis. The biological basis for this differential vulnerability is unknown, although differences in transcriptional dysfunction caused by mutant huntingtin (mhtt) have been proposed as a possible mechanism. In order to determine the differences in gene expression caused by mhtt in these two populations, we selectively isolated translated mRNAs from striatopallidal and striatonigral MSNs in the R6-2 and YAC128 HD mouse models at pre- and post-symptomatic time points using the BACTRAP technique (Heiman et al, 2008). We re-characterized the behavioral phenotype of the HD model mice on the D1 and D2 TRAP backgrounds and found many changes in the translated mRNA profiles of these two classes of medium spiny neurons, including known changes in the literature as well as novel pathways. One novel pathway was sphingosine-1-phosphate (S1P) signaling. Because the S1P-receptor G-protein coupled receptor 6 (GPR6) is enriched in striatopallidal cells, we hypothesized that changes in this pathway might play a role in striatopallidal medium spiny neuron vulnerability. Using mass spectrometry, we have shown that S1P levels, as well as other complex sphingolipid species, are decreased in the striatum of R6-2 mice early in disease progression. We have preliminary evidence to suggest Sphk2 and Sgpl1, the enzymes responsible for the production and degradation of S1P, are altered in HD mouse models in patterns that might explain the changes in S1P levels. We have shown that S1P can have pro-survival effects in an in vitro model of striatal origin. Together, these results implicate alterations in S1P signaling in the pathogenesis of Huntington’s Disease and offer an approach for moving from clinical observations of a disease toward the beginning of a mechanistic understanding of the underlying causes of specific cell vulnerability in other diseases