Statins are common drugs that are clinically used to reduce elevated plasma cholesterol levels. Based on their solubility, statins are considered to be either hydrophilic or lipophilic. Amongst them, simvastatin has the highest lipophilicity to facilitate its ability to cross the blood-brain barrier. Recent studies have suggested that simvastatin could be a promising therapeutic option for different brain complications and diseases ranging from brain tumors (i.e., medulloblastoma and glioblastoma) to neurological disorders (i.e., Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease). Specific mechanisms of disease amelioration, however, are still unclear. Independent studies suggest that simvastatin may reduce the risk of developing certain neurodegenerative disorders. Meanwhile, other studies point towards inducing cell death in brain tumor cell lines. In this review, we outline the potential therapeutic effects of simvastatin on brain complications and review the clinically relevant molecular mechanisms in different cases.

Metformin is a commonly used drug for treating type 2 diabetes. Metformin is an inexpensive drug with low/no side effects and is well tolerated in human patients of different ages. Recent therapeutic strategies for human disease have considered the benefits of drug repurposing. This includes the use of the anti-diabetic drug metformin. Accordingly, the anti-inflammatory, anti-cancer, anti-viral, neuroprotective, and cardioprotective potentials of metformin have deemed it a suitable candidate for treating a plethora of human diseases. As results from preclinical studies using cellular and animal model systems appear promising, clinical trials with metformin in the context of non-diabetes-related illnesses have been started. Here, we aim to provide a comprehensive overview of the therapeutic potential of metformin in different animal models of human disease and its suggested relationship to epigenetics and ailments with epigenetic components.

The human lysine acetyltransferases KAT3A ( CREBBP) and KAT3B ( EP300) are essential enzymes in gene regulation in the nucleus. Their ubiquitous expression in metazoan cell types controls cell proliferation and differentiation during development. This comprehensive review delves into the biological roles of KAT3A and KAT3B in neurodevelopment, shedding light on how alterations in their regulation or activity can potentially contribute to a spectrum of neurodegenerative diseases (e.g., Huntington's and Alzheimer's). We explore the pathophysiological implications of KAT3 function loss in these disorders, considering their conserved protein domains and biochemical functions in chromatin regulation. The discussion also underscores the crucial role of KAT3 proteins and their substrates in supporting the integration of key cell signaling pathways. Furthermore, the narrative highlights the interdependence of KAT3-mediated lysine acetylation with lysine methylation and arginine methylation. From a cellular perspective, KAT3-dependent signal integration at subnuclear domains is mediated by liquid–liquid phase separation in response to KAT3-mediated lysine acetylation. The disruption of these finely tuned regulatory processes underscores their pathological roles in neurodegeneration. This review also points to the exciting potential for future research in this field, inspiring further investigation and discovery in the area of neurodevelopment and neurodegenerative diseases.

This article explores the complex interplay between the process of protein translation and DNA methylation, discussing their combined involvement in brain development. We will emphasize on DNA methylation and related proteins such as DNMTs, TETs, and MeCP2, the latter being the prototype of DNA methyl-binding proteins. Collectively, DNA methylation machinery may be involved in controlling the cell fate commitment of brain cells, as well as their neuronal and glial lineage specification. We aim to summarize current knowledge on the dynamics of protein translation, ribosome biogenesis, and relevant cellular pathways, including the mTOR signaling, in the context of brain development. Special attention is given to MeCP2 because of its unique role as an epigenetic factor that influences the chromatin states with a link to protein translation and its relevance to human disease. We also discuss the impact of DNA methylation-mediated chromatin regulation and protein translation in neurodevelopmental disorders. Our discussions include multi-omics techniques and integrative mechanisms that connect DNA methylation with protein translation.

Methyl CpG-binding protein 2 (MeCP2) is an epigenetic reader of DNA methylation with high abundance in the brain. While genetic mutations occur across different protein domains of MeCP2, the T158M mutation is amongst the most frequent MeCP2 mutations. MeCP2 is encoded by the MECP2/Mecp2 gene located on the X chromosome. In humans, MECP2 mutations cause Rett Syndrome, a debilitating neurodevelopmental disorder in females, with very rare cases presenting in males. Despite the generation of different transgenic mouse lines with MeCP2 mutations, the sex-dependent phenotypic and molecular impact of common MeCP2 mutations in mouse models of disease remains largely unexplored. Here, we focus on the MeCP2 T158M mutation using Mecp2^tm4.1Bird/J transgenic mice (referred to as Mecp2^T158M), and report that Mecp2^T158M mutant mice display sex-specific molecular, behavioural, and phenotypic characteristics when compared to wild-type controls. Our data indicates sex- and brain-region-dependent impacts on the expression of MeCP2, synaptic proteins, cytoskeletal markers, and autophagy factors. Our findings demonstrate that the phenotypic and molecular characteristics of this mouse model may relate to the clinical manifestation in human patients with Rett Syndrome.