Project 458978

Leukodystrophies (LDs) are a group of rare genetic neurological diseases that primarily affect children, resulting in progressive disability and ultimately death. Although individually rare, altogether, they affect approximately 1 in 4733 children, with no curative treatments currently available. Hypomyelinating leukodystrophies (HLDs) are a subset of LDs affecting the development of myelin in the brain. Myelin acts to insulate neurons allowing for the fast conduction of nerve impulses in the brain. Improper functioning of some genes can lead to defects in myelin formation. One of the genes causing an HLD is EPRS1, which plays a role in protein production. Genes produce important proteins by two processes: transcription and translation. Translation involves building a protein using its constituents: the amino acids. EPRS1's role is crucial in ensuring that two amino acids are properly integrated in the proteins. Genetic variants (or mistakes) in other genes involved in protein synthesis (i.e. transcription and translation) have been associated with HLDs, highlighting the importance of proper protein production during myelination. However, the link between EPRS1 and HLDs remains to be determined. We hypothesize that improper functioning of EPRS1 affects the cell types in the brain responsible for producing myelin, known as oligodendrocytes (OLs). OLs are tasked with myelinating the brain, a demanding and energetic process. Therefore, improper functioning of EPRS1 can affect the ability of OLs to myelinate during a critical developmental window. This project will create a disease model of EPRS1-HLD using patient-derived cells to investigate the impact of EPRS1 function on OLs and how this contributes to the disease. Advancements in understanding EPRS1-HLD will set the groundwork for future research aiming at developing treatments for this rare devastating disease.