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.
Highlights
AGC1 deficiency, focusing on refractory epilepsy and postnatal hypomyelination observed in both AGC1-deficient humans and mice as well as the failure to synthesize Gln in astrocytes [7], and DA mishandling in the nigrostriatal pathway [20] seen in aralar-KO mice
AGC1-deficiency in humans, mostly due to mutant ARALAR with defective transport activity, provokes the “early infantile encephalopathy 39” (EIEE39) inducing a neurodevelopmental arrest similar to that observed in the aralar-KO mice, which represent a good model for studying the human disease
Neurons highly express aralar and depend on the ARALAR-malate-aspartate shuttle (MAS) pathway for energy metabolism with glucose as substrate. Neuronal functions such as the Asp and NAA synthesis, lactate consumption, respiration and the response to small Ca2+ signals mediating the Ca2+ -induced activation of the mitochondrial metabolism are dependent on ARALAR-MAS activity
Summary
Since aralar-KO mice recapitulate main hallmarks of the human disease, including neurodevelopmental arrest, epilepsy and severethehypomyelination was described more than developmental arrest, seizures, epileptic activity in hippocampus [19,20] and hypomyeten years ago [10]; and, more recently, other AGC1 deficient patients with early infantile lination [4,21], the experimental work with these mice (lacking MAS activity in brain) has epileptic encephalopathy reported [11,12,13,14,15,16,17,18]. Will be further discussed to better understand the metabolic transcellular fluxes in brain and the metabolic requirements in the different brain cell types affected by the lack of AGC1-MAS activity
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