Transcriptomic profiling of glia in Huntington's disease

Abstract

Huntington’s disease (HD) is a severely debilitating, autosomal dominant neurodegenerative disease with a fatal outcome. There is accumulating evidence of a prominent role of glia in the pathology of HD, and we investigated this by conducting single nuclear RNA sequencing of human post mortem brain in 4 regions; caudate nucleus, frontal cortex, hippocampus and cerebellum. Across 127,205 nuclei from HD patients and age and sex matched controls, we found an altered heterogeneity of glia in HD. We describe prominent changes in gene expression and abundance of certain subtypes of astrocytes, microglia, oligodendrocyte precursor cells and oligodendrocytes between HD and control samples, and these differences are widespread across brain regions. Furthermore, we highlight two possible mechanisms that characterise the glial contribution to disease pathology. Firstly, we show that upregulation of molecular chaperones represents a cross-glial signature in HD, which likely reflects an adaptive response to the aggregation of Huntingtin protein and might promote cell survival. Secondly, we show an oligodendrocyte-specific upregulation of the calmodulin-dependent 3’,5’-cyclic nucleotide phosphodiesterase 1A (PDE1A) in HD compared to controls, which could cause dysfunction to key cellular functions through its downregulation of the important second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Our results support the hypothesis that glia have an independent role in the pathology of HD, and we show that all types of glia are affected in the disease. As glia are selfrenewing and therefore more tractable for treatment than neurons, our findings may be of therapeutic relevance.