Epigenetic Mechanism and Therapeutic Approaches in Huntington’s Disease
DOI:
https://doi.org/10.54097/xxa1ws81Keywords:
Huntington’s Disease, mechanism, treatment.Abstract
Huntington’s Disease (HD) is a severe neurodegenerative disorder in which epigenetic mechanisms, such as DNA methylation, histone modifications, and non-coding RNAs, play pivotal roles in its pathogenesis and progression. Abnormal DNA methylation patterns in HD may silence or dysregulate critical genes in the human brain, leading to neuronal dysfunction. Histone acetylation is disrupted by the impairment of CREB-binding protein (CBP), thus altering chromatin structure and impacting essential expression pathways that support neuronal survival. Non-Coding RNAs are yet another prolific branch of epigenetics, exhibiting a variety of duties and properties; in HD, microRNAs, long non-coding RNAs, and other ncRNAs can calibrate or undermine neuronal gene expression, making an impression in the HD scene. Accordingly, a myriad of therapeutic strategies either target or utilize the epigenetic mechanisms in HD. From CRISPR/dCas9 tools that can precisely modify DNA methylation at specific loci, to histone de-acetylase inhibitors that restore histone acetylation balance, to emerging ncRNA-targeted or ncRNA-participating therapies, these strategies develop divergently, with a range of success throughout these different approaches. Although many of these advances face challenges in delivery and specificity, epigenetic therapeutics show great potential in combating HD.
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References
[1] “Huntington’s Disease.” National Institute of Neurological Disorders and Stroke, 2024.
[2] Irfan, Zainab, et al. “Pathogenesis of Huntington’s Disease: An Emphasis on Molecular Pathways and Prevention by Natural Remedies.” Brain Sciences, vol. 12, no. 10, Multidisciplinary Digital Publishing Institute, Oct. 2022, pp. 1389–89.
[3] Horvath, Steve, et al. “Huntington’s Disease Accelerates Epigenetic Aging of Human Brain and Disrupts DNA Methylation Levels.” Aging, vol. 8, no. 7, Impact Journals LLC, July 2016, pp. 1485–512.
[4] Wang, Fengli, et al. “Genome-Wide Loss of 5-HmC Is a Novel Epigenetic Feature of Huntington’s Disease.” Human Molecular Genetics, vol. 22, no. 18, Oxford University Press, May 2013, pp. 3641–53.
[5] Izaskun Villar-Menéndez, et al. “Increased 5-Methylcytosine and Decreased 5-Hydroxymethylcytosine Levels Are Associated with Reduced Striatal A2AR Levels in Huntington’s Disease.” NeuroMolecular Medicine, vol. 15, no. 2, Springer Science+Business Media, Feb. 2013, pp. 295–309.
[6] Lu, Ake T., et al. “DNA Methylation Study of Huntington’s Disease and Motor Progression in Patients and in Animal Models.” Nature Communications, vol. 11, no. 1, Nature Portfolio, Sept. 2020.
[7] Mollica, Peter A., et al. “Epigenetic Alterations Mediate IPSC-Induced Normalization of DNA Repair Gene Expression and TNR Stability in Huntington’s Disease Cells.” Journal of Cell Science, vol. 131, no. 13, The Company of Biologists, June 2018.
[8] Gojanovich, Aldana D., et al. “Abnormal Synaptic Architecture in IPSC-Derived Neurons from a Multi-Generational Family with Genetic Creutzfeldt-Jakob Disease.” Stem Cell Reports, vol. 19, no. 10, Cell Press, Sept. 2024, pp. 1474–88.
[9] Chen, Xiufei, et al. “Mapping Epigenetic Modifications by Sequencing Technologies.” Cell Death and Differentiation, Springer Nature, Sept. 2023.
[10] Jiang, Haibing, et al. “Depletion of CBP Is Directly Linked with Cellular Toxicity Caused by Mutant Huntingtin.” Neurobiology of Disease, vol. 23, no. 3, Sept. 2006, pp. 543–51.
[11] JC; “Mutant Huntingtin Represses CBP, but Not P300, by Binding and Protein Degradation.” Molecular and Cellular Neurosciences, vol. 30, no. 4, Mol Cell Neurosci, 2015. Accessed 2 Jan. 2025.
[12] Giralt, A., et al. “Long-Term Memory Deficits in Huntington’s Disease Are Associated with Reduced CBP Histone Acetylase Activity.” Human Molecular Genetics, vol. 21, no. 6, Oxford University Press, Nov. 2011, pp. 1203–16.
[13] Das, Eashita, et al. “MicroRNA-124 Targets CCNA2 and Regulates Cell Cycle in STHdh/Hdh Cells.” Biochemical and Biophysical Research Communications, vol. 437, no. 2, Elsevier BV, July 2013, pp. 217–24.
[14] Das, Eashita, et al. “Delayed Cell Cycle Progression in STHdhQ111/HdhQ111 Cells, a Cell Model for Huntington’s Disease Mediated by MicroRNA-19a, MicroRNA-146a and MicroRNA-432.” MicroRNA, vol. 4, no. 2, Bentham Science Publishers, Oct. 2015, pp. 86–100.
[15] Kocerha, Jannet, et al. “MicroRNA-128a Dysregulation in Transgenic Huntington’s Disease Monkeys.” Molecular Brain, vol. 7, no. 1, Springer Science and Business Media LLC, June 2014.
[16] Xu, Ya-Jie, et al. “Regulatory Networks between Polycomb Complexes and Non-Coding RNAs in the Central Nervous System.” Journal of Molecular Cell Biology, vol. 12, no. 5, Oxford University Press, June 2019, pp. 327–36.
[17] Huang, Wanxu, et al. “LncRNA-Mediated DNA Methylation: An Emerging Mechanism in Cancer and Beyond.” Journal of Experimental & Clinical Cancer Research, vol. 41, no. 1, BioMed Central, Mar. 2022.
[18] Shin, Jun Wan, et al. “Allele-Specific Silencing of the Gain-of-Function Mutation in Huntington’s Disease Using CRISPR/Cas9.” JCI Insight, vol. 7, no. 19, American Society for Clinical Investigation, Aug. 2022.
[19] Liao, Hsin-Kai, et al. “In Vivo Target Gene Activation via CRISPR/Cas9-Mediated Trans-Epigenetic Modulation.” Cell, vol. 171, no. 7, Cell Press, Dec. 2017, pp. 1495-1507.e15.
[20] Pan, Yanchun, et al. “Inhibition of DNA Methyltransferases Blocks Mutant Huntingtin-Induced Neurotoxicity.” Scientific Reports, vol. 6, no. 1, Nature Portfolio, Aug. 2016.
[21] MacDonald, Marcy E., et al. “The Huntington’s Disease Candidate Region Exhibits Many Different Haplotypes.” Nature Genetics, vol. 1, no. 2, Nature Portfolio, May 1992, pp. 99–103.
[22] Valor, Luis, et al. “Lysine Acetyltransferases CBP and P300 as Therapeutic Targets in Cognitive and Neurodegenerative Disorders.” Current Pharmaceutical Design, vol. 19, no. 28, Bentham Science Publishers, July 2013, pp. 5051–64.
[23] Harrison, Ian F., and David T. Dexter. “Epigenetic Targeting of Histone Deacetylase: Therapeutic Potential in Parkinson’s Disease?” Pharmacology & Therapeutics, vol. 140, no. 1, Elsevier BV, May 2013, pp. 34–52.
[24] Jia, Haiqun, et al. “The Effects of Pharmacological Inhibition of Histone Deacetylase 3 (HDAC3) in Huntington’s Disease Mice.” PLoS ONE, vol. 11, no. 3, Public Library of Science, Mar. 2016, pp. e0152498–98.
[25] Chiu, Chi-Tso, et al. “Combined Treatment with the Mood Stabilizers Lithium and Valproate Produces Multiple Beneficial Effects in Transgenic Mouse Models of Huntington’s Disease.” Neuropsychopharmacology, vol. 36, no. 12, Springer Nature, July 2011, pp. 2406–21.
[26] Vitolo, Ottavio V., et al. “Amyloid β-Peptide Inhibition of the PKA/CREB Pathway and Long-Term Potentiation: Reversibility by Drugs That Enhance CAMP Signaling.” Proceedings of the National Academy of Sciences, vol. 99, no. 20, Proceedings of the National Academy of Sciences, Sept. 2002, pp. 13217–21
[27] Brillante, Simona, et al. “Advances in MicroRNA Therapeutics: From Preclinical to Clinical Studies.” Human Gene Therapy, vol. 35, no. 17-18, Mary Ann Liebert, Inc., Aug. 2024, pp. 628–48.
[28] Caron, Nicholas S., et al. “Potent and Sustained Huntingtin Lowering via AAV5 Encoding MiRNA Preserves Striatal Volume and Cognitive Function in a Humanized Mouse Model of Huntington Disease.” Nucleic Acids Research, Oxford University Press, Oct. 2019.
[29] Kotowska-Zimmer, Anna, et al. “A CAG Repeat-Targeting Artificial MiRNA Lowers the Mutant Huntingtin Level in the YAC128 Model of Huntington’s Disease.” Molecular Therapy - Nucleic Acids, vol. 28, June 2022, pp. 702–15
[30] Hoss, Andrew G., et al. “Study of Plasma‐Derived MiRNAs Mimic Differences in Huntington’s Disease Brain.” Movement Disorders, vol. 30, no. 14, Wiley, Nov. 2015, pp. 1961–64.
[31] Winkle, Melanie, et al. “Noncoding RNA Therapeutics — Challenges and Potential Solutions.” Nature Reviews Drug Discovery, vol. 20, no. 8, Springer Science and Business Media LLC, June 2021, pp. 629–51.
[32] Driscoll, Rachelle, et al. “Dose-Dependent Reduction of Somatic Expansions but Not Htt Aggregates by Di-Valent SiRNA-Mediated Silencing of MSH3 in HdhQ111 Mice.” Scientific Reports, vol. 14, no. 1, Nature Portfolio, Jan. 2024.
[33] Li, Kun, and Ziqiang Wang. “LncRNA NEAT1: Key Player in Neurodegenerative Diseases.” Ageing Research Reviews, vol. 86, Elsevier BV, Feb. 2023, pp. 101878–78.
[34] Tamblin-Hopper, Phoebe, et al. “The Potential Therapeutic Applications of Long Non-Coding RNAs.” Journal of Translational Genetics and Genomics, vol. 8, no. 2, June 2024, pp. 225–43.
[35] Niu, Dun, et al. “Circular RNA Vaccine in Disease Prevention and Treatment.” Signal Transduction and Targeted Therapy, vol. 8, no. 1, Springer Nature, Sept. 2023.
[36] Romano, Silvia, et al. “Circulating U13 Small Nucleolar RNA as a Potential Biomarker in Huntington’s Disease: A Pilot Study.” International Journal of Molecular Sciences, vol. 23, no. 20, Multidisciplinary Digital Publishing Institute, Oct. 2022, pp. 12440–40.
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