To evaluate whether the observed phenotypes can be ameliorated, we evaluated genetic reduction of an E3 SUMO ligase, PIAS1, based on our previous data showing that reduced Pias1 expression resulted in: decreased aberrant accumulation of mHTT in R6/2 HD mice, rescued transcriptional deficits in zQ175 HD mice, particularly of synaptic genes, and improved mitochondrial DNA integrity and synaptic gene expression in iPSC-neurons36,38. Here, PIAS1 is linked to Huntington disease.