Glutaminase C overexpression in the brain induces learning deficits, synaptic dysfunctions, and neuroinflammation in mice

Abstract

Glutaminolysis, a metabolic process that converts glutamine to glutamate, is particularly important for the central nervous system since glutamate is the major transmitter of excitatory synapses. Glutaminase is the mitochondrial enzyme that catalyzes the first step of glutaminolysis. Two genes encode at least four isoforms of glutaminase in humans. GLS1 gene encodes isoforms kidney-type glutaminase and glutaminase C (GAC) through alternative splicing, whereas GLS2 gene encodes liver-type glutaminase isoforms. KGA and GAC have been associated with several neurological diseases. However, it remains unclear whether changes in their expressions can directly cause brain abnormalities. Using a transgenic approach, we generated mice that overexpressed GAC in the brain. The resulting transgenic mice had severe impairments in spatial and fear learning compared with littermate controls. The learning deficits were consistent with diminished hippocampal long-term potentiation in the hippocampal slices of the GAC transgenic mice. Furthermore, we found increases in astrocyte and microglia markers, inflammatory factors, and a decrease in synapse marker synaptophysin, suggesting neuroinflammation and synaptic changes in the GAC transgenic mouse brains. In conclusion, these findings provide the first evidence that GAC overexpression in the brain has deleterious effects on learning and synaptic integrity in vivo.

HSP60 silencing promotes Warburg-like phenotypes and switches the mitochondrial function from ATP production to biosynthesis in ccRCC cells

“…3D). This is consistent with an earlier report describing that GAC is essential to the mitochondrial glutamine metabolism in cancer cells [[29], [30], [31]]. We further treated cells with the GLS1 inhibitor BPTES and discovered that HSP60 silencing sensitized cells to GLS1 inhibition (Fig.…”

The Glutamate System as a Crucial Regulator of CNS Toxicity and Survival of HIV Reservoirs

“…Also, the level of GLS isoform C was elevated in HIV-1-positive post-mortem brains which may be a compensatory effect induced by chronic exacerbate levels of Glu (Huang et al, 2011 ). The GLS C overexpression is also correlated with several neurocognitive and neurodegenerative disorders (Wang et al, 2017 ). The overproduction of Glu during HIV-1 infection in monocyte-derived macrophage (MDM) is caused by the release of GLS from the mitochondria followed by the generation of oxidative stress (Erdmann et al, 2009 ; Tian et al, 2012 ).…”

Glutaminase 1 regulates the release of extracellular vesicles during neuroinflammation through key metabolic intermediate alpha-ketoglutarate

“…Our previous work demonstrated the role of GLS1 in the regulation of EV release [ 17 ]. However, the mechanism of how GLS1 regulates the release remains unclear.…”

“…To determine the link between the GLS1 and the secretion of EVs in vivo, we used a GLS1 transgenic mouse model that we recently generated [ 17 ]. The transgenic mice have GLS1 isoform GAC overexpressed in all cells of the neural lineage.…”