Progressive neurodegenerative diseases typified by expansions of polyglutamine (polyQ) repeats tend to have a relatively focused etiology, with an emphasis on post-translational protein dysregulation underlying the pathology. Huntington's disease (HD) is an inherited late-onset polyQ disorder, in which the offending mutant protein, huntingtin (Htt), is susceptible to proteolytic cleavage, phosphorylation and/or aggregation during the disease progression; somehow, these changes relate to the death of neurons. An additional conductor of the HD orchestra has been proposed; evidence also implicates transcriptional dysregulation as an important component in disease progression. It has been postulated that aggregates of Htt might alter basal transcriptional levels of key housekeeping proteins and, thereby, compromise the function and health of neurons. Important insight into how this might occur has now been provided in a study showing Htt interaction with, and inhibition of, histone acetyltransferases. Histone acetylation is associated with an open, transcriptionally active chromatin state, whereas deacetylation is correlated with a closed chromatin state and gene repression or silencing. Steffan et al. [1xHistone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Steffan, J.S. et al. Nature. 2001; 413: 739–743Crossref | PubMed | Scopus (831)See all References[1] now show that deacetylase activity contributes to the neurodegeneration stimulated by Htt with polyQ repeats and deacetylase (HDAC) inhibitors can slow neurodegeneration in an invertebrate model of HD.Previous findings had indicated that mutant Htt interacts directly with the CREB-binding protein (CBP), which contains an acetyltransferase domain and is a component of a protein complex that acts on many promoters to activate genes. A protein fragment corresponding to exon 1 of Htt, containing the polyQ repeats (Httex1p), causes HD-like pathology in mice and inhibits, through direct binding, the acetyltransferase activity of a number of proteins. The interaction is not dependent on the polyQ regions found naturally in the acetyltransferases, but is dependent on the length of the polyQ sequence found in the Httex1p fragment, suggesting that a targeted, gain of inhibitory function is endowed upon Httex1p by polyQ extension. To verify the direct acetyltransferase inhibitory activity of Httex1p in cells, two approaches were taken. First, cells were transfected with polyQ Httex1p and the degree of histone acetylation, but not histone protein expression, was shown to be decreased, an effect that was reversed when HDAC inhibitors were applied also. Second, Drosophila photoreceptor neurons engineered to express either polyQ Httex1p or polyQ peptides in vivo degenerate progressively, but display a dose-dependent increase in vitality when HDAC inhibitors were also fed to flies. Inhibitor-treated adult flies exhibited a repressed early-onset death; early-onset death is observed following polyQ Httex1p expression. A partial loss of function allele for the gene Sin3A, which encodes a protein component of HDAC complexes in Drosophila, also increased the viability of and reduced neurodegeneration in polyQ-Httex1p-containing flies.Studies have shown that CBP and other transcriptional regulatory proteins are sequestered in cytoplasmic and nuclear aggregates, both in HD mouse models and in the brains of HD patients. Locking away the key architects of higher order chromatin design and gene transcription probably lead to a repression of those genes required normally to keep neurons functional and viable. Time will tell whether HDAC inhibitors will prove to be possible pharmacological sources of novel neurodegeneration therapeutics. When administered to flies already demonstrating neurodegeneration, the inhibitors arrest further degeneration markedly, indicating an effect on the cause, rather than just the symptoms, of the disease. Roll on the rodent model!
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Jul 1, 2020
Yang Gao + 9
Open Access
