Huntington Disease (HD) is a neurodegenerative disorder hallmarked by the expression of a mutant form of the huntingtin gene (mHtt). A therapeutic goal for HD treatment involves the restoration of neurobiological pathways disrupted by mHtt. Pridopidine, an investigational HD drug candidate, has been shown to improve motor symptoms in both preclinical models as well as in HD patients. While originally described as a dopaminergic stabilizer, in vitro binding studies show highest affinity of pridopidine to the sigma-1 receptor. We previously reported that pridopidine upregulates BDNF, glucocorticoid receptor (GR), and dopamine 1 receptor (D1R) signaling pathways in WT rat striatum. To expand on these findings and explore molecular changes specific to HD, we repeated this study in a YAC128 HD mouse model whereby mice were treated with pridopidine or vehicle starting at postnatal week 6 and sacrificed after 11.5 months of age. We then performed RNAseq data analysis on the striatum. We identified 1346 differentially expressed genes (DEGs) in vehicle treated YAC128 mice vs. healthy controls, 221 DEGs in YAC128 mice treated with 30 mg/kg of pridopidine vs. vehicle, and 73 DEGs in YAC128 mice treated with 10 mg/kg of pridopidine vs. vehicle (all adj.p<0.05). In addition, the previously reported pridopidine-induced upregulation of BDNF, GR, and D1R pathways was confirmed after treatment with either dose (adj.p<0.05), and alternatively spliced genes after 30 mg/kg of pridopidine compared to YAC128 vehicle are enriched for the BDNF pathway (adj.p<0.05). Further, pathway analysis of DEGs after 30 mg/kg dosage revealed enrichment for biological processes related to synaptic transmission, including upregulation in the key HD-impaired processes – cAMP and calcium signaling (adj.p<0.05). Lastly, since mHtt was shown to induce neurotoxicity by promoting M1 microglia that secrete proinflammatory cytokines, enrichment analysis tested for microglial markers. Treatment with 30 mg/kg of pridopidine led to the downregulation of genes associated with M1 activation (adj.p<0.05). To summarize, pridopidine induces transcriptional modifications reversing genes in HD-impaired pathways involved in neuronal transmission and protection in the YAC128 striatum.
