Transcriptional dysregulation in Huntington's disease: a failure of adaptive transcriptional homeostasis

Abstract

Huntington's disease (HD) is a signature polyglutamine disorder. An enduring theory of HD pathogenesis has involved dysregulation of transcription. Indeed, transcriptional regulatory proteins can be modulated to overcome cardinal features of HD-modeled mice, and efforts to move these into human studies are ongoing. Here, we discuss a unifying hypothesis emerging from these studies, which is that HD represents the pathological disruption of evolutionarily conserved adaptive gene programs to counteract oxidative stress, mitochondrial dysfunction and accumulation of misfolded proteins. Transcriptional dyshomeostasis of adaptive genes is further exacerbated by repression of genes involved in normal synaptic activity or growth factor signaling.

Figure 1

Known mechanisms of mutant huntingtin (mHtt)-mediated transcriptional dysregulation in Huntington’s disease. After cleavage via either caspase-6 activity or ser-16 phosphorylation, toxic N-terminal fragments of mHtt translocate into the nucleus and form toxic intranuclear aggregates of N-terminal Htt fragments. These, in turn, can influence different components of the transcriptional process such as genomic DNA, histones, basal transcriptional machinery [a complex of RNA polymerase II (RNAP II), transcription initiation factor (TAF)II130, TATA binding protein (TBP), TFIIF, TFIID, etc.], transcription factors (TF), transcriptional corepressors (CR), or transcriptional coactivators (CA) and so on (highlighted in yellow), to cause transcriptional dysregulation.

Figure 2

Model depicting Huntington’s disease as a failure of adaptive transcriptional homeostasis leading to persistent bioenergetic, oxidative and proteotoxic stress. Abbreviations: ER, endoplasmic reticulum; mHtt, mutant Huntingtin.