The chapter provides an overview of the recent breakthroughs in the understanding of the role of epigenetic mechanisms, such as histone posttranslational modifications and DNA methylation, in the onset and progression of two neurodegenerative disorders, Huntington’s disease and amyotrophic lateral sclerosis. We also summarize the latest advances in the development of safe and effective therapeutic approaches based on the modulation of epigenetic mechanisms in these disorders. In particular, preclinical investigation proved the ability of several histone deacetylase inhibitors and compounds targeting DNA methylation to slow disease progression and improve clinical parameters. Elucidating the epigenetic components of neurodegeneration may also lead to the identification of disease-specific signatures, paving the way for the discovery of new biological markers.
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