Glutaminase kidney isoform, mitochondrial

Glutaminase kidney isoform (GLS) is a mitochondrial enzyme that catalyzes glutamine catabolism, playing a critical role in renal acid-base homeostasis and regulating glutamate levels as the brain's primary excitatory neurotransmitter (UniProt: O94925). The protein is expressed across multiple tissues and its enzymatic activity directly impacts neurotransmitter homeostasis in the central nervous system.

GLS is associated with several severe neurodevelopmental and neurological disorders. Mutations cause Developmental and Epileptic Encephalopathy 71 (DEE71), an autosomal recessive condition with neonatal seizure onset and high mortality, as well as CASGID syndrome, characterized by cataract, skin inflammation, developmental delay, and cerebral glutamate excess (UniProt: O94925). A third condition, Global Developmental Delay, Progressive Ataxia, and Elevated Glutamine (GDPAG), involves progressive neurologic deterioration with persistently elevated plasma glutamine.

In Alzheimer's disease, GLS is significantly downregulated in post-mortem AD brain tissue compared to age-matched controls (mean log2FC: −0.63), based on quantitative proteomics of subcellular fractions (Chaparral AD proteomics). This reduction may reflect altered glutamate metabolism and excitatory neurotransmission in AD pathology.