Abstract
Although it has been known for over 30 years that CAG trinucleotide repeat expansions in the HTT gene are the cause of Huntington's disease (HD), it is still not understood how these mutations lead to the loss of striatal spiny projection neurons (SPNs) and other vulnerable neuronal cell types in HD. Here we show that SCN4B , a gene that is enriched in neurons that influence motor function, including striatal SPNs, modulates HD-associated phenotypes in vivo . Loss of Scn4b in wild-type mice mimics and Scn4b overexpression in an HD mouse model rescues several HD-associated phenotypes, including motor and cognitive deficits. Single nucleus RNA sequencing (snRNA-seq) analysis reveals that loss of Scn4b replicates several HD-associated gene expression signatures in the striatum. Conversely, overexpression of Scn4b rescues HD gene expression signatures and improves various SPN electrophysiological properties in HD model mice. Taken together, our results implicate loss of Scn4b expression as an important contributor to HD pathogenesis and therapeutic target in HD.