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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/215684
G9a, a histone lysine methylatransferase, as a potential target for Alzheimer’s disease
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[eng] Alzheimer’s disease (AD) is the most common cause of dementia that currently lacks effective pharmacological treatment. Identifying new targets to halt disease progression is a pressing need. In most cases, AD has a complex etiology likely to involve multiple susceptibility genes and environmental factors. Epigenetics plays a crucial role in linking the genome to the environment and regulating the transcription of genes related to learning and memory. In particular, G9a is a histone lysine methyltransferase identified as having a critical role in various neurodegenerative diseases, including AD.
On the one hand, I first conducted a study to confirm the involvement of G9a in the neurodegenerative processes that underlie the Senescence Accelerated Mouse-Prone 8 (SAMP8) model at both a behavioural and molecular level. Secondly, we demonstrated the efficacy of G9a inhibition as a therapy for AD using the SAMP8 mouse. We identified its main altered pathways and a novel mechanism of action based on Glia maturation factor beta (GMFB) modulation. The third study validated additional epigenetic mechanisms, specifically microRNAs, that participate in AD and are present in the SAMP8 model. These mechanisms were reversed after the inhibition of G9a. Notably, the downregulation of miRNA-128 after G9ai partially explains the modulations of pathways related to Peroxisome proliferator-activated receptor gamma (PPARγ).
On the other hand, given the problems associated with G9a inhibitors (G9ai), such as toxicity, poor blood-brain barrier (BBB) permeability, and selectivity, it was decided to focus efforts on the search for chemical structures that would overcome these challenges. The fourth study involved structure- based virtual screening and in vitro and in vivo screening of the chosen compounds. This screening shows that a candidate with promising results in in vitro and in vivo studies, FLAV-27, is under patent. Optimization and characterization studies for FLAV-27 are being developed in our Knowledge Industry projects. In addition, the Multi Target Directed Ligands (MTDL)-based approach shows attractive advantages for multifactorial diseases such as AD. Therefore, we have also conducted in silico studies to obtain dual G9a/ Glycogen synthase kinase-3 beta (GSK-3β) compounds. In vivo studies were shown with Caenorhabitis elegans (C. elegans) and SAMP8, demonstrating their potential for AD. This doctoral thesis presents results for candidate T2, who is currently in the patent process. Finally, the drug discovery process is characteristically expensive and lengthy. Therefore, the fifth article focuses on the repurposing technique, which is often less risky, more cost-effective, and can be completed in less time. An in silico study proposed a cancer drug, Raltitrexed, as a possible G9ai. This work evaluated its efficacy in inhibiting G9a through in vitro and in vivo studies using the C. elegans model. The results suggest that Raltitrexed could be a candidate for treating AD, although further experiments are required.
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BELLVER SANCHIS, Aina. G9a, a histone lysine methylatransferase, as a potential target for Alzheimer’s disease. [consulta: 3 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/215684]