Epigenetic Mechanism and Therapeutic Approaches in Huntington’s Disease

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.