Abstract
Huntington’s Disease (HD) is a fatal neurodegenerative disorder caused by the expansion of a polyglutamine-coding CAG repeat in the Huntingtin gene. One of the main causes of neurodegeneration in HD is transcriptional dysregulation that, in part, is caused by the inhibition of histone acetyltransferase (HAT) enzymes. HD pathology can be alleviated by increasing the activity of specific HATs or by inhibiting histone deacetylase (HDAC) enzymes. To determine which histone’s post-translational modifications (PTMs) might play crucial roles in HD pathology, we investigated the phenotype-modifying effects of PTM mimetic mutations of variant histone H3.3 in a Drosophila model of HD. Specifically, we studied the mutations (K→Q: acetylated; K→R: non-modified; and K→M: methylated) of lysine residues K9, K14, and K27 of transgenic H3.3. In the case of H3.3K14Q modification, we observed the amelioration of all tested phenotypes (viability, longevity, neurodegeneration, motor activity, and circadian rhythm defects), while H3.3K14R had the opposite effect. H3.3K14Q expression prevented the negative effects of reduced Gcn5 (a HAT acting on H3K14) on HD pathology, while it only partially hindered the positive effects of heterozygous Sirt1 (an HDAC acting on H3K14). Thus, we conclude that the Gcn5-dependent acetylation of H3.3K14 might be an important epigenetic contributor to HD pathology.
Funder
National Research, Development and Innovation Office
New National Excellence Program of the Ministry for Innovation and Technology
the Hungarian Academy of Sciences
the Bloomington Drosophila Stock Center
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
Reference52 articles.
1. Huntington Disease;Bates;Nat. Rev. Dis. Primer,2015
2. Loss of Huntingtin Function Slows Synaptic Vesicle Endocytosis in Striatal Neurons from the HttQ140/Q140 Mouse Model of Huntington’s Disease;McAdam;Neurobiol. Dis.,2020
3. Polyglutamine Repeats in Neurodegenerative Diseases;Lieberman;Annu. Rev. Pathol.,2019
4. Huntington’s Disease: Mechanisms of Pathogenesis and Therapeutic Strategies;Licitra;Cold Spring Harb. Perspect. Med.,2017
5. Kaltenbach, L.S., Romero, E., Becklin, R.R., Chettier, R., Bell, R., Phansalkar, A., Strand, A., Torcassi, C., Savage, J., and Hurlburt, A. (2007). Huntingtin Interacting Proteins Are Genetic Modifiers of Neurodegeneration. PLoS Genet., 3.
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