Single-Nucleus RNA-Seq Reveals Dysregulation of Striatal Cell Identity Due to Huntington's Disease Mutations

Abstract

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by a trinucleotide expansion in exon 1 of the huntingtin (HTT) gene. Cell death in HD occurs primarily in striatal medium spiny neurons (MSNs), but the involvement of specific MSN subtypes and of other striatal cell types remains poorly understood. To gain insight into cell type-specific disease processes, we studied the nuclear transcriptomes of 4524 cells from the striatum of a genetically precise knock-in mouse model of the HD mutation, Htt Q175/1 , and from wild-type controls. We used 14-to 15-month-old male mice, a time point at which multiple behavioral, neuroanatomical, and neurophysiological changes are present but at which there is no known cell death. Thousands of differentially expressed genes (DEGs) were distributed across most striatal cell types, including transcriptional changes in glial populations that are not apparent from RNA-seq of bulk tissue. Reconstruction of cell type-specific transcriptional networks revealed a striking pattern of bidirectional dysregulation for many cell type-specific genes. Typically, these genes were repressed in their primary cell type, yet de-repressed in other striatal cell types. Integration with existing epigenomic and transcriptomic data suggest that partial loss-of-function of the polycomb repressive complex 2 (PRC2) may underlie many of these transcriptional changes, leading to deficits in the maintenance of cell identity across virtually all cell types in the adult striatum.

Microarray profiling of hypothalamic gene expression changes in Huntington’s disease mouse models

“…Striatal transcriptional dysregulation is one of the hallmarks of HD [36][37][38] and specific gene expression changes using qRT-PCR have also been reported in the HD hypothalamus [39][40][41].…”

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

“…Drd1 is downregulated in dSPNs of HD models (Fig. 5A,C,D), reflecting their loss of transcriptomic identities 36 . However, another strong marker of dSPNs, Ebf1 , a well-known factor contributing to dSPNs differentiation 37, 38 , was upregulated in dSPNs (i.e., M-D1 and S-D1, Fig.…”

Striatal Control of Movement: A Role for New Neuronal (Sub-) Populations?

“…Secondly, they deciphered a transcriptional gradients coding for both the anatomical location of a given SPNs, as well as its compartmental identity. Additionally, most studies confirmed the existence of transcriptionally defined eSPNs or eSPN-like D1-Pcdh8-neurons (Gokce et al, 2016 ; Saunders et al, 2018 ; Anderson et al, 2020 ; Malaiya et al, 2020 ; Stanley et al, 2020 ), D1/D2-SPNs (Gokce et al, 2016 ; Martin et al, 2019 ; Anderson et al, 2020 ; Stanley et al, 2020 ) and exopatch neurons (Smith et al, 2016 ; Martin et al, 2019 ; Figure 1B ).…”

“…The gene set to identify dSPNs includes, for example, Drd1a (the gene coding for the D1 receptor), Tac1 and Isl1 , whereas the set to identify iSPNs includes Drd2 (coding for the D2 receptor), Adora2a , Penk , Gpr6 , Gpr52 , and SP9 . These sets enabled a discrete and robust separation of the “classical” SPNs, and similar ones were used in subsequent studies (Ho et al, 2018 ; Saunders et al, 2018 ; Martin et al, 2019 ; Malaiya et al, 2020 ; Stanley et al, 2020 ). Secondly, it also reported a small group of D1/D2 SPNs.…”