The primary focus of this research is on motor neuron disorders (MND), including spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). These disorders are severe, with a major symptom being the degeneration of motor neurons. Motor neurons are essential for the central nervous system, responsible for transmitting signals from the brain to muscles throughout the body. When these neurons degenerate or die, it leads to muscle weakness, paralysis, and eventually can be life-threatening. A significant aspect of this MANTIS project is the investigation of DNA methylation, a biological process where a methyl group (a specific chemical structure) is added to DNA. This process significantly affects gene expression without changing the actual DNA sequence. In the context of MND, alterations in DNA methylation patterns have been observed, but the exact role and mechanisms of these changes are not well understood. Understanding these epigenetic changes (changes in gene expression caused by factors other than changes in the DNA sequence) is crucial because they could be key drivers in the progression of these diseases or potential targets for treatment.
The importance of this research for society cannot be understated. SMA and ALS, as part of MNDs, pose significant challenges not only to the individuals directly affected but also to their families, healthcare systems, and society at large. These diseases often lead to a rapid decline in the quality of life, as patients lose their ability to perform everyday tasks and become increasingly dependent on others. This results also in substantial economic burdens due to medical costs and loss of productivity.
Moreover, these diseases currently have limited treatment options. In the case of SMA, the currently approved treatment achieves survival milestone but complete muscle function restoration remains limited. Understanding the underlying mechanisms, especially the role of DNA methylation in these diseases, could pave the way for the development of new, more effective treatments.
The project has several ambitious but crucial objectives centered on understanding and potentially manipulating the process of DNA methylation to treat or prevent MNDs.
Firstly, the project aims to define precisely how DNA methylation and demethylation regulate gene expression in SMA. This involves mapping the specific changes in DNA methylation patterns and understanding how these changes affect the functioning of genes involved in motor neuron health and survival. By identifying these patterns, researchers hope to pinpoint specific genes or pathways that could be targeted in treatments.
Secondly, the research focuses on the role of TET enzymes, which are involved in converting methylated cytosines (5mC) in DNA to hydroxymethylated cytosines (5hmC), a change that can influence gene expression. The interaction of these enzymes with motor neuron pathology, specifically in relation to the Survival of Motor Neuron (SMN1) protein, is of particular interest. SMN1 is crucial in SMA, as its deficiency leads to motor neuron death. Understanding how TET enzymes interact with SMN1 could reveal new therapeutic targets or strategies.
Finally, the project seeks to establish the potential of using targeted demethylation as a therapeutic strategy. This involves using advanced technologies like CRISPR/Cas9 to specifically alter DNA methylation at targeted genomic locations. The goal is to reverse or correct the disease-related epigenetic profiles, potentially restoring normal gene function and rescuing motor neuron health.
