A037 Decoding neuronal vulnerability: integrative analysis of D1r- and D2r-Msns responses in Huntington’s disease

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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 2 (D2R) medium-sized spiny neurons (MSNs), exhibit an increased susceptibility to the CAG-repeat expansion mutation (figure 1).1 2 To unravel differences between D2R- and D1R-MSNs, we employed a multidimensional approach, integrating transcriptional, morphological, genomic, and somatic instability analyses. Specifically, we resourced to Htt CAG knock-in mouse models harbouring 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 transcriptomic analyses following FACS-sorting of dissociated MSNs, revealed distinct gene expression profiles, indicating a significant upregulation of oxidative phosphorylation and translation pathways in D1R-MSNs at pre-symptomatic stage. Secondly, morphological analyses revealed an outnumbering of D1R-MSNs in the HD condition, particularly in the ventral-medial striatum. Interestingly, D2R-MSNs instead, present an increased nuclear accumulation of mutant huntingtin aggregates. Finally, while no large copy number variations were detected at genomic level in either population, a significant greater somatic instability in D2R-MSNs was noted as early as 8 weeks of age. In summary, our integrative study suggests that the distinct vulnerability of MSNs in HD might result from a combination of an early transcriptional compensatory-response of D1R neurons together with an early susceptibility of D2R neurons, correlated to increased somatic instability and mutant huntingtin aggregation. In this work we detected various differential properties of D1R- and D2R-MSNs upon the HD mutation. At pre-symptomatic stage, both the MSNs populations manifest a downregulation of LINE-1 retrotransposable elements. For what concerns gene expression, D1R-MSNs present several transcriptional differences in HD condition compared to control, particularly involving an up-regulation of oxidative phosphorylation (OXPHOS) and translation pathways. Conversely, D2R-MSNs do not activate strong transcriptional changes upon HD mutation. However, D2R-MSNs present already at pre-symptomatic stage a greater CAG tract somatic expansion, and at more advanced age a propensity to accumulate more aggregated nuclear mutant huntingtin compared to D1R neurons. Overall, these different features might contribute to the already reported earlier degeneration of D2R-MSNs. References Halliday GM, et al. Regional specificity of brain atrophy in Huntington’s disease. Experimental Neurology 1998;154:663–672. Sapp E, et al. Evidence for a preferential loss of enkephalin immunoreactivity in the external globus pallidus in low grade Huntington’s disease using high resolution image analysis. Neuroscience 1995;64:397–404. Floreani L, et al. Analysis of LINE1 Retrotransposons in Huntington’s Disease. Front Cell Neurosci 2021;15:743797.

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