AGC1 Deficiency: Pathology and Molecular and Cellular Mechanisms of the Disease

Abstract

AGC1/Aralar/Slc25a12 is the mitochondrial carrier of aspartate-glutamate, the regulatory component of the NADH malate-aspartate shuttle (MAS) that transfers cytosolic redox power to neuronal mitochondria. The deficiency in AGC1/Aralar leads to the human rare disease named “early infantile epileptic encephalopathy 39” (EIEE 39, OMIM # 612949) characterized by epilepsy, hypotonia, arrested psychomotor neurodevelopment, hypo myelination and a drastic drop in brain aspartate (Asp) and N-acetylaspartate (NAA). Current evidence suggest that neurons are the main brain cell type expressing Aralar. However, paradoxically, glial functions such as myelin and Glutamine (Gln) synthesis are markedly impaired in AGC1 deficiency. Herein, we discuss the role of the AGC1/Aralar-MAS pathway in neuronal functions such as Asp and NAA synthesis, lactate use, respiration on glucose, glutamate (Glu) oxidation and other neurometabolic aspects. The possible mechanism triggering the pathophysiological findings in AGC1 deficiency, such as epilepsy and postnatal hypomyelination observed in humans and mice, are also included. Many of these mechanisms arise from findings in the aralar-KO mice model that extensively recapitulate the human disease including the astroglial failure to synthesize Gln and the dopamine (DA) mishandling in the nigrostriatal system. Epilepsy and DA mishandling are a direct consequence of the metabolic defect in neurons due to AGC1/Aralar deficiency. However, the deficits in myelin and Gln synthesis may be a consequence of neuronal affectation or a direct effect of AGC1/Aralar deficiency in glial cells. Further research is needed to clarify this question and delineate the transcellular metabolic fluxes that control brain functions. Finally, we discuss therapeutic approaches successfully used in AGC1-deficient patients and mice.

Intracellular Citrate/acetyl-CoA flux and endoplasmic reticulum acetylation: Connectivity is the answer

“…Loss-of-function mutations in SLC25A1 are also associated with neurodevelopmental deficits and intellectual disability, intractable seizures, severe metabolic alterations, and early death [ 34 , 35 ]. Genetic variations affecting SLC25A12 have been associated with ASD and developmental forms of epileptic encephalopathy [ [36] , [37] , [38] , [39] , [40] ], while genetic variations in SLC25A13 have been associated with different metabolic disorders that manifest with severe neurological symptoms [ 41 ]. These observations show that genetic alterations affecting the two most important systems that control crosstalk between the mitochondrial and the cytosolic malate/citrate/acetyl-CoA pathways appear to be linked to severe neurological disorders, highlighting a fundamental role in normal brain development and function.…”

SLC25A12 Missense Variant in Nova Scotia Duck Tolling Retrievers Affected by Cerebellar Degeneration—Myositis Complex (CDMC)

“…This disease is characterized by global developmental delay, seizures, hypotonia with poor motor function, and hypomyelination on brain imaging. Analogous to the process in knockout mice, the myelination defect is speculated to reflect the impaired supply of NAA to oligodendrocytes caused by SLC25A12 deficiency [ 18 ].…”