Abstract
Huntington’s Disease (HD) is a devastating neurodegenerative disorder that is caused by an expanded CAG trinucleotide repeat in the Huntingtin (HTT) gene. Transcriptional dysregulation in the human HD brain has been documented but is incompletely understood. Here we present a genome-wide analysis of mRNA expression in human prefrontal cortex from 20 HD and 49 neuropathologically normal controls using next generation high-throughput sequencing. Surprisingly, 19% (5,480) of the 28,087 confidently detected genes are differentially expressed (FDR<0.05) and are predominantly up-regulated. A novel hypothesis-free geneset enrichment method that dissects large gene lists into functionally and transcriptionally related groups discovers that the differentially expressed genes are enriched for immune response, neuroinflammation, and developmental genes. Markers for all major brain cell types are observed, suggesting that HD invokes a systemic response in the brain area studied. Unexpectedly, the most strongly differentially expressed genes are a homeotic gene set (represented by Hox and other homeobox genes), that are almost exclusively expressed in HD, a profile not widely implicated in HD pathogenesis. The significance of transcriptional changes of developmental processes in the HD brain is poorly understood and warrants further investigation. The role of inflammation and the significance of non-neuronal involvement in HD pathogenesis suggest anti-inflammatory therapeutics may offer important opportunities in treating HD.
Highlights
Huntington’s Disease (HD) is a devastating neurodegenerative disorder characterized clinically by involuntary choreic movement, personality changes, and premature death[1,2]
Widespread Differential Expression Changes Are Observed in HD
More genes are overexpressed in HD versus control than are underexpressed
Summary
Huntington’s Disease (HD) is a devastating neurodegenerative disorder characterized clinically by involuntary choreic movement, personality changes, and premature death[1,2]. The disease is caused by an expanded CAG repeat in the Huntingtin gene (HTT)[3] that produces selective neuronal loss in the brain[4]. Individuals commonly present characteristic motor signs in midlife with a mean onset age of 40 years[5]. No therapy to date has definitively delayed onset or subsequent progression of these symptoms. Most studies in HD are conducted using model systems, (i.e. cell lines or mouse models) or peripheral human biospecimens such as blood and not in involved brain regions from human HD affected individuals. While collecting and analyzing human post-mortem samples presents challenges, the study of brain regions involved in HD provides relevant insight into the disease pathogenesis
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