Multiple Aspects of Gene Dysregulation in Huntington's Disease

Abstract

Huntington's Disease (HD) is a genetic neurodegenerative disease caused by a CAG expansion in the gene encoding Huntingtin (Htt). It is characterized by chorea, cognitive, and psychiatric disorders. The most affected brain region is the striatum, and the clinical symptoms are directly correlated to the rate of striatal degeneration. The wild-type Htt is a ubiquitous protein and its deletion is lethal. Mutated (expanded) Htt produces excitotoxicity, mitochondrial dysfunctions, axonal transport deficit, altered proteasome activity, and gene dysregulation. Transcriptional dysregulation occurs at early neuropathological stages in HD patients. Multiple genes are dysregulated, with overlaps of altered transcripts between mouse models of HD and patient brains. Nuclear localization of Exp-Htt interferes with transcription factors, co-activators, and proteins of the transcriptional machinery. Another key mechanism described so far, is an alteration of cytoplasmic retention of the transcriptional repressor REST, which is normally associated with wild-type Htt. As such, Exp-Htt causes alteration of transcription of multiple genes involved in neuronal survival, plasticity, signaling, and mitochondrial biogenesis and respiration. Besides these transcriptional dysregulations, Exp-Htt affects the chromatin structure through altered post-translational modifications (PTM) of histones and methylation of DNA. Multiple alterations of histone PTM are described, including acetylation, methylation, ubiquitylation, polyamination, and phosphorylation. Exp-Htt also affects the expression and regulation of non-coding microRNAs (miRNAs). First multiple neural miRNAs are controlled by REST, and dysregulated in HD, with concomitant de-repression of downstream mRNA targets. Second, Exp-Htt protein or RNA may also play a major role in the processing of miRNAs and hence pathogenesis. These pleiotropic effects of Exp-Htt on gene expression may represent seminal deleterious effects in the pathogenesis of HD.

Keywords: REST; chromatin remodeling; epigenetics; histone modifications; miRNAs; transcription.

Figure 1

Illustration of a signaling pathway involved in histone PTMs in HD. Under normal conditions, activation of nuclear MSK-1 induces phosphorylation of (1) histone H3 and (2) the transcriptional factor CREB. Phosphorylated CREB recruits CBP, and activates its histone acetyl transferase (HAT) properties. Post-translational modifications (PTM) of histones (phosphorylation, acetylation) lead to modification of chromatin structure from heterochromatin to euchromatin, which allows gene transcription to occur. One of the key genes regulated by CREB is PGC1α, a crucial gene involved for the regulation of mitochondrial and metabolic functions. In Huntington’s disease, Exp-Htt expression results on (1) down-regulation of MSK-1 expression and (2) sequestration of CREB and CBP within Exp-Htt aggregates. Therefore, the heterochromatin structure is favored, a structure that impairs transcription of CREB target genes.

Figure 2

REST-mediated gene repression is favored in HD. Wild-Type Htt interacts with REST, a transcriptional repressor, within the cytoplasm. This leads to de-repression of REST target genes like BDNF or non-coding miRNAs, which are essential for neuronal survival, neuronal plasticity or dendrites growth. Expansion of Htt disrupts its binding with REST and facilitates nuclear entry of REST along with the formation of the repressor complex on the RE1 site. Activation of RE1 site results on target gene silencing and participates to neuro-degeneration.