Glutamate dehydrogenase 1 and SIRT4 regulate glial development

Abstract

Congenital hyperinsulinism/hyperammonemia (HI/HA) syndrome is caused by an activation mutation of glutamate dehydrogenase 1 (GDH1), a mitochondrial enzyme responsible for the reversible interconversion between glutamate and α-ketoglutarate. The syndrome presents clinically with hyperammonemia, significant episodic hypoglycemia, seizures, and a frequent incidences of developmental and learning defects. Clinical research has implicated that although some of the developmental and neurological defects may be attributed to hypoglycemia, some characteristics cannot be ascribed to low glucose and as hyperammonemia is generally mild and asymptomatic, there exists the possibility that altered GDH1 activity within the brain leads to some clinical changes. GDH1 is allosterically regulated by many factors, and has been shown to be inhibited by the ADP-ribosyltransferase sirtuin 4 (SIRT4), a mitochondrially localized sirtuin. Here we show that SIRT4 is localized to mitochondria within the brain. SIRT4 is highly expressed in glial cells, specifically astrocytes, in the postnatal brain and in radial glia during embryogenesis. Furthermore, SIRT4 protein decreases in expression during development. We show that factors known to allosterically regulate GDH1 alter gliogenesis in CTX8 cells, a novel radial glial cell line. We find that SIRT4 and GDH1 overexpression play antagonistic roles in regulating gliogenesis and that a mutant variant of GDH1 found in HI/HA patients accelerates the development of glia from cultured radial glia cells.

NAD and ADP‐ribose metabolism in mitochondria

“…Physiologically, the SIRT4‐dependent decrease in GDH activity was found to repress amino acid‐stimulated insulin secretion both in cell culture systems and mouse SIRT4 knockout models. The recent observation that GDH and SIRT4 antagonistically influence the growth of glial cells corroborates the importance of this regulatory cycle . ADP‐ribosylation of GDH is reversible.…”

Glutamate Metabolism in the Brain Focusing on Astrocytes

“…The enzyme is highly regulated by ADP and leucine both of which function as allosteric activators and by GTP, which acts as an allosteric inhibitor (Spanaki et al 2012). Emerging evidence suggests that GDH can be allosterically inhibited by mitochondrial SIRT4 (silent information regulator 4) that is highly expressed during brain development (Komlos et al 2013, Lavu et al 2008). Humans express two isoforms of the enzyme (GDH1 and GDH2) that differ dramatically with regard to the allosteric regulation; other mammals express only the housekeeping isoform, GDH1 (Spanaki et al 2012).…”

Histone deacetylases (HDACs) and brain function

“…Further support for the role of acetylation in brain development comes from studies showing that the class III HDAC SIRT1 is critical for driving the differentiation of cells toward an astroglial lineage, away from a neuronal fate Prozorovski et al, 2008. However, nonacetylation roles of HDACs may also be critical in brain development because the class III HDAC SIRT4 that shows no deacetylase activity also appears to play a significant role in the development of astroglia from radial glia, in association with glutamate dehydrogenase-1 (Komlos et al, 2013). Indeed, SIRT4 is highly expressed in astrocytes in the postnatal brain and in radial glia in embryonic tissues, whereas expression decreases during development.…”