AGC-1 deficiency, a rare genetic demyelinating and neurodegenerative disease: a study on oligodendrocyte precursor cells in cell lines, a mouse model and human iPS-derived brain cells

AGC1-deficiency is a rare genetic neurodegenerative disease caused by defects in the SLC25A12 gene encoding for a mitochondrial aspartate-glutamate carrier, important in the metabolism of brain amino acids and myelin synthesis. AGC1 mutations lead to drastic reduction of carrier activity, which results in hypotonia, developmental delay, intractable epilepsy and cortical atrophy with altered myelin formation in the CNS, most likely due to a dramatic reduction of N-acetyl aspartate levels in the brain. The aim of this thesis was to study the molecular mechanisms underlying AGC1-deficiency in appropriate in vitro (oligodendrocyte precursor cells) and in vivo (SLC25A12 heterozygous knockout mice) disease models in particular by focusing on oligodendrocyte precursor alterations to better define pathogenetic mechanisms that could potentially lead to identify new interesting therapeutic targets. Furthermore, our study focused on the evaluation of Neural Stem Cells proliferation and differentiation in neuronal and glia cells, both astrocytes and oligodendrocytes, in neurospheres derived from the subventricular zone of our mouse model. Lastly, preliminary experiments have been performed on NSCs derived from induced Pluripotent Stem cells from AGC1-deficiency patients and healthy controls, in order to further validate our data in human cells. All results showed a proliferation deficit of OPCs that was not due to mitochondrial biochemical alterations, but rather associated with an alteration of trophic factors essential for maintaining the balance between oligodendrocyte proliferation and differentiation, mainly PDGFα and TGFβ. These results supported that alterations induced by AGC1 reduced activity could impair the physiological cross-talk mediated by growth factors between neurons and OPCs necessary for OPCs proliferation and neuronal survival. The importance of this study lies also on the fact that mitochondrial dysfunction is at the basis not only of AGC1-deficiency, but also of other neurodegenerative and demyelinating diseases, some of which are rare, while others are widely spread, such as multiple sclerosis.