Huntington's disease (HD) is caused by the expansion of a CAG repeat within exon 1 of the huntingtin (HTT) gene, resulting in an expanded polyglutamine stretch that forms insoluble aggregates associated with neuronal dysfunction and cell death. Because transcriptional dysregulation is part of the complex pathogenesis of HD, histone deacetylases (HDACs) have been evaluated as therapeutic targets. HDAC4 is a transcriptional repressor that shuttles between the nucleus and cytoplasm and represses the transcription of genes with a role in neuronal cell death. HDAC4 is thought to self-aggregate through its glutamine-rich N terminus. Bates and colleagues now show that HDAC4 associates with mutant HTT in vivo in a polyglutamine-length–dependent manner and colocalizes with cytoplasmic inclusions in the brains of HD mouse models. HDAC4 depletion inhibited cytoplasmic aggregate formation in HD mice, and this was accompanied by a pronounced restoration of synaptic function. In addition, knockdown of HDAC4 partially restored motor coordination and other neurological phenotypes and extended lifespan, thus suggesting a substantial contribution of cytoplasmic HTT aggregation to the pathology of HD. HDAC4 did not relocalize to the nucleus during disease progression, and HDAC4 knockdown had no effect on global transcriptional dysregulation and did not modulate nuclear HTT aggregation. Altogether, the data suggest a crucial role for cytoplasmic HTT aggregation in HD pathogenesis and identify HDAC4 as a promising therapeutic target. (PLoS Biol. doi:10.1371/journal.pbio.1001717, 26 November 2013)