Masala, Alessandra (2017) Epigenetic modifications associated with Amyotrophic Lateral Sclerosis (ALS) onset and progression. Doctoral Thesis.
In the recent years a growing amount of evidence indicates the functional significance of epigenetics in various aspects of neural function and dysfunction. Alterations in chromatin structure resulting in long lasting changes in gene expression have been associated to many different aspects of neuronal biology, including neurodegenerative disorders such Amyotrophic Lateral Sclerosis (ALS). ALS is predominantly sporadic and environmental triggers may be involved in disease initiation. In this respect, the epigenome can provide the key to transform the genetic information into phenotype. Alterations in the epigenetic machinery and/or epigenetic modifications can be considered a readout of disease onset and progression and an ideal target for therapeutic interventions. My PhD thesis is, indeed, focused on different aspect of epigenetic modifications in ALS cellular and animal models. By in vitro and in vivo assays I demonstrate that some epigenetic markers, linked to transcriptional activation or repression, are selectively altered in cellular and animal model of ALS. Moreover I observed a physical interaction between the ALS-causing gene TDP43 and the histone deacetylases 1 (HDAC1). Finally, I demonstrate that perturbation of HDAC1 level or activity affects TDP-43-induced cell damage. Although preliminary, these data can be extended by testing more specific HDAC1 inhibitors which can be chemically optimized by computational biology approaches.
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