Huntington’s disease is caused by the elongation of the polyQ region of the protein huntingtin, resulting in mutant Huntingtin or mHtt. Current research indicates that the main contributions of mHtt in causation of the symptoms of Huntington’s Disease, are formation of protein aggregates and the alteration of Htt regulated transcription.
The aggregates that form from mHTT, are caused by what Dr. Max Perutz described as a polar zipper. The polar zipper is formed when the N-terminal, containing the Poly Q region, is cleaved from the protein by a protease, the enzymes responsible for protein cleavage. The fragments formed from cleavage then hydrogen bond to each other to form the aggregate. The aggregate elicits toxicity to both the nucleus and the cytoplasm, causing some of the cellular damage associated with Hunitington’s Disease. (Perandones, Micheli, and Radrizzani 2010) While the mechanism for how the aggregates cause cellular damage is not completely understood, the leading hypothesis is that the formation of the truncated mutant huntingtin aggregates exceeds the cells ability to break them down using the proteosome or autophagosome. Thus the adult onset of Huntington’s Disease is attributed to slowing of cellular functions that are supposed to breakdown the toxic HD aggregates. (Martinez-Vicente et al. 2010)
The other leading cause of cellular dysfunction is the dysregulation of transcription associated with mutant Huntingtin. Huntingtin regulates an extensive net of enzymes responsible for the epigenetics of the cell via mechnisms that methylate and acetylate DNA and histones as seen in Figure 2.
At the level of transcription there is evidence that mHtt effects the regulation of cystathione y-lyase (CSE) the enzyme responsible for the biosynthesis of the amino acid, cysteine. In the proposed pathway, mHtt inhibits the function of specificity protein 1, a known transcriptional activator of CSE. The subsequent inhibition of CSE, is implicated in diminished levels of cysteine, which increases oxidative stress and contributes to the disease state of striatal cells. (Paul et al. 2014)
H3K4me3 (trimethylation of lysine 4 on histone 3) is a histone modification that signals active transcription start sites. The strength of the H3K4me3 signal is strongly correlated with the level of gene expression within a cell. Using ChiP seq, a method to analyze protein-DNA interaction, the H3K4me3 signal for active transcription was compared between Htt wildtype individuals and individual with Huntington’s Disease. Epigenetic dysregulation was evident in HD individuals, as H3K4me3 was reduced subsequently leading to the reduction of the mRNA of genes in close proximity to the H3K4me3 transcription start site. (Dong et al. 2015)