snRNA-seq of Huntington’s disease mice reveals vulnerability profiles of cortical cell types

A common feature of neurodegeneration is selective vulnerability, where certain neurons succumb to disease, while others remain spared. The molecular underpinnings of these differences remain elusive. Here, we performed transcriptomic profiling of the motor cortex in a mouse model of Huntington’s disease (HD), an incurable hereditary movement disorder caused by a CAG repeat expansion in the Huntingtin gene. Strikingly, single-nucleus RNA-sequencing revealed a clear transcriptomic separation of HD and control samples within the vulnerable glutamatergic, but not disease-resistant GABAergic cell clusters. Tissue sampling at different time points allowed us to delineate a two-stage disease trajectory with distinct changes at early and late stages. Analysis of differentially expressed genes demonstrated progressive dysregulation of neuronal cell-type identity and upregulation of ER-phagy receptors. Mechanistic investigations in cellular HD models revealed increased ER-phagy, while knockdown of the ER-phagy receptor Tex264 resulted in elevated levels of the ER stress marker BiP, suggesting a protective role of ER-phagy in HD. Taken together, these findings advance our understanding of differential neuronal vulnerability, and identify ER-phagy as a new pathway in HD pathogenesis.