Mitochondrial
aspartate-glutamate carrier isoform 1 (
AGC1) deficiency is an ultra-rare
genetic disease characterized by global hypomyelination and brain
atrophy, caused by mutations in the SLC25A12 gene leading to a reduction in AGC1 activity. In both neuronal precursor cells and oligodendrocytes precursor cells (NPCs and OPCs), the AGC1 determines reduced proliferation with an accelerated differentiation of OPCs, both associated with gene expression dysregulation. Epigenetic regulation of gene expression through
histone acetylation plays a crucial role in the proliferation/differentiation of both NPCs and OPCs and is modulated by mitochondrial metabolism. In
AGC1 deficiency models, both OPCs and NPCs show an altered expression of
transcription factors involved in the proliferation/differentiation of brain precursor cells (BPCs) as well as a reduction in
histone acetylation with a parallel alteration in the expression and activity of
histone acetyltransferases (HATs) and
histone deacetylases (HDACs). In this study,
histone acetylation dysfunctions have been dissected in in vitro models of
AGC1 deficiency OPCs (Oli-Neu cells) and NPCs (neurospheres), in physiological conditions and following pharmacological treatments. The inhibition of HATs by
curcumin arrests the proliferation of OPCs leading to their differentiation, while the inhibition of HDACs by
suberanilohydroxamic acid (SAHA) has only a limited effect on proliferation, but it significantly stimulates the differentiation of OPCs. In NPCs, both treatments determine an alteration in the commitment toward glial cells. These data contribute to clarifying the molecular and epigenetic mechanisms regulating the proliferation/differentiation of OPCs and NPCs. This will help to identify potential targets for new therapeutic approaches that are able to increase the OPCs pool and to sustain their differentiation toward oligodendrocytes and to myelination/remyelination processes in
AGC1 deficiency, as well as in other white matter neuropathologies.