Finding new targets to counteract brain progenitor cells dysregulation in AGC1 deficiency hypomyelination: a multi-disciplinary approach.

AGC1 deficiency is an ultra-rare genetic disease leading to a severe encephalopathy in the early childhood. This neurological disease is caused by mutations in the SLC25A12 gene, which encodes the isoform 1 of mitochondrial aspartate/glutamate carrier (AGC1). Patients show arrested psychomotor development, seizures, cerebral atrophy and a global hypomyelination with a marked reduction in N-Acetyl-Aspartate (NAA), a crucial precursor for myelin formation in the brain. No cure is currently available and the molecular mechanisms of the disease are still unclear. We have previously demonstrated an essential role of AGC1 in regulating the proliferation of neuron- and oligodendrocyte-precursor cells, the main brain cell types involved in myelination, as well as in sustaining NAA synthesis, potentially explaining patients’ clinical symptoms. The project aims to clarify the biochemical, molecular and epigenetic mechanisms influencing myelination dysfunction in new and more appropriate cellular models of the disease from mice or from the differentiation of patients’ iPSCs. In these models, we will identify, through molecular and computational biology, transcriptional and epigenetic targets potentially influencing myelination, as well as the altered cytosolic and mitochondrial pathways, through biochemistry and metabolomic approach. Finally, we will demonstrate the validity of identified targets through in vitro proof of concept experiments. This multidisciplinary approach will help to unravel the altered mechanisms leading to dysregulation of myelination in AGC1 deficiency, thus indicating the potential targets to counteract hypomyelination and eventually to develop more appropriate and personalized therapies for AGC1 deficiency patients. Furthermore, considering that AGC1 deficiency shares many clinical features with other rare neurological diseases, including hypomyelination, these targets could be also tested in other similar pathologies.