ABSTRACT: Understanding the molecular mechanisms driving selective neuronal vulnerability to different neurodegenerative disorders remains a crucial, but unsolved question. Here we explored the case of Huntington's disease (HD), where the striatum and, specifically, dopamine receptor 1 (D1R) and dopamine receptor 2 (D2R) medium-sized spiny neurons (MSNs), exhibit differential susceptibility to the HTT CAG-repeat expansion mutation, with D2R-neurons being impacted earlier and more significantly. To unravel differences between D2R and D1R MSNs, we employed a multidimensional approach, integrating genomic, transcriptional, morphological, and somatic instability analyses. Specifically, we used Htt CAG knock-in mouse models harboring 18 (HttQ20: “control”) or ~190 (HttQ175: “HD”) consecutive CAG repeats, expressing tdTomato and EGFP under the control of Drd1 and Drd2 promoters, respectively. First, comprehensive genomic and transcriptomic analyses following fluorescence-activated cell sorting of dissociated striatal neurons, revealed no large copy number variations, but distinct gene expression profiles, indicating a significant upregulation of oxidative phosphorylation and translation pathways in D1R positive neurons at pre-symptomatic stage. Secondly, morphological analyses revealed a greater proportion of D1R-positive neurons compared to D2R-positive neurons in HD mice, particularly in the ventral-medial striatum, with D2R-positive neurons presenting an increased nuclear accumulation of mutant huntingtin aggregates. In summary, our integrative study suggests that the distinct vulnerability of MSNs in HD might result from a combination of an early transcriptional compensatory/buffering-response of D1R neurons together with specific susceptibility of D2R neurons.
