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Glutamate Dehydrogenase as a Neuroprotective Target Against Neurodegeneration

Authors
Kim, AY  | Baik, EJ
Citation
Neurochemical research, 44(1). : 147-153, 2019
Journal Title
Neurochemical research
ISSN
0364-31901573-6903
Abstract
Regulation of glutamate metabolism via glutamate dehydrogenase (GDH) might be the promising therapeutic approach for treating neurodegenerative disorders. In the central nervous system, glutamate functions both as a major excitatory neurotransmitter and as a key intermediate metabolite for neurons. GDH converts glutamate to alpha-ketoglutarate, which serves as a TCA cycle intermediate. Dysregulated GDH activity in the central nervous system is highly correlated with neurological disorders. Indeed, studies conducted with mutant mice and allosteric drugs have shown that deficient or overexpressed GDH activity in the brain can regulate whole body energy metabolism and affect early onset of Parkinson's disease, Alzheimer's disease, temporal lobe epilepsy, and spinocerebellar atrophy. Moreover, in strokes with excitotoxicity as the main pathophysiology, mice that overexpressed GDH exhibited smaller ischemic lesion than mice with normal GDH expression. In additions, GDH activators improve lesions in vivo by increasing alpha-ketoglutarate levels. In neurons exposed to an insult in vitro, enhanced GDH activity increases ATP levels. Thus, in an energy crisis, neuronal mitochondrial activity is improved and excitotoxic risk is reduced. Consequently, modulating GDH activity in energy-depleted conditions could be a sound strategy for maintaining the mitochondrial factory in neurons, and thus, protect against metabolic failure.
Keywords
MeSH

DOI
10.1007/s11064-018-2467-1
PMID
29357018
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Physiology
Ajou Authors
김, 아영  |  백, 은주
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