Huntington’s Disease Produces Multiplexed Transcriptional Vulnerabilities of Striatal D1-D2 and Striosome-Matrix Neurons

Abstract

Striatal cell-type-specific vulnerability in Huntington’s disease (HD) preferentially affects dopamine D2R-expressing projection neurons (SPNs), compatible with manifest motor symptomatology in HD. Transcriptional studies of striatal striosome-matrix compartmentalization in HD are, however, limited, despite pathologic evidence for striosome vulnerability aligning with early mood symptomatology. We used single-nucleus RNA-sequencing on striatal samples from two murine models, and rare Grade 1 HD patient tissues, to examine striosome and matrix sub-clusters within parent D1 and D2 SPN clusters. In human HD, striosomal SPNs were the most depleted SPN population. Surprisingly, for both mouse models, transcriptomic distinctiveness was diminished more for striosome-matrix SPNs than for D1-D2 SPNs. Compartmental markers were dysregulated so as to cancel endogenous identities as striosomal or matrix SPNs, but markers for D1-D2 exhibited less identity obscuring. The canonical striosome-matrix as well as D1-D2 organizations of the striatum thus are both strongly, but differentially, compromised in HD and are targets for therapeutics.

In humans, striato-pallido-thalamic projections are largely segregated by their origin in either the striosome-like or matrix-like compartments

“…Numerous disorders that were hypothesized to have a compartment-specific element to their pathology and progression may be more completely understood when studied in a compartment-specific approach, rather than at the wholestriatum level (Crittenden and Graybiel, 2011). For example, early in the clinical course of Huntington disease (HD) MSNs in the striosome degenerate more than those in matrix (Hedreen and Folstein, 1995;Matsushima, 2022). Striosome-dominated degeneration also holds true in later stages of HD for individuals whose symptoms were moodpredominant (Tippett et al, 2007).…”

In humans, insulo-striate structural connectivity is largely biased toward either striosome-like or matrix-like striatal compartments

“…However, a recent report found that Lypd1, a peptide marker of VENs, 77 is also selectively enriched in the striosome. 78 If future studies demonstrate that VENs selectively project to the striosome, this association may serve as a substrate for limbic symptoms in compartment-selective neurodegenerative diseases. 16,81 4.5: Relating biases in structural connectivity to functional specialization…”