The discovery of human of GLUD2 glutamate dehydrogenase and its implications for cell function in health and disease.

While the evolutionary changes that led to traits unique to humans remain unclear, there is increasing evidence that enrichment of the human genome through DNA duplication processes may have contributed to traits such as bipedal locomotion, higher cognitive abilities and language. Among the genes that arose through duplication in primates during the period of increased brain development was GLUD2, which encodes the hGDH2 isoform of glutamate dehydrogenase expressed in neural and other tissues. Glutamate dehydrogenase GDH is an enzyme central to the metabolism of glutamate, the main excitatory neurotransmitter in mammalian brain involved in a multitude of CNS functions, including cognitive processes. In nerve tissue GDH is expressed in astrocytes that wrap excitatory synapses, where it is thought to play a role in the metabolic fate of glutamate removed from the synaptic cleft during excitatory transmission. Expression of GDH rises sharply during postnatal brain development, coinciding with nerve terminal sprouting and synaptogenesis. Compared to the original hGDH1 (encoded by the GLUD1 gene), which is potently inhibited by GTP generated by the Krebs cycle, hGDH2 can function independently of this energy switch. In addition, hGDH2 can operate efficiently in the relatively acidic environment that prevails in astrocytes following glutamate uptake. This adaptation is thought to provide a biological advantage by enabling enhanced enzyme catalysis under intense excitatory neurotransmission. While the novel protein may help astrocytes to handle increased loads of transmitter glutamate, dissociation of hGDH2 from GTP control may render humans vulnerable to deregulation of this enzyme's function. Here we will retrace the cloning and characterization of the novel GLUD2 gene and the potential implications of this discovery in the understanding of mechanisms that permitted the brain and other organs that express hGDH2 to fine-tune their functions in order to meet new challenging demands. In addition, the potential role of gain-of-function of hGDH2 variants in human neurodegenerative processes will be considered.