The 594 amino acid propeptide of glutamate decarboxylase 1 is coded by 16 exons of the GAD1 gene at 2q31.1. It's predominant isoform of four formed by alternative spicing is GAD-67 and is critical to the metabolism of GABA, the major inhibitory neurotransmitter in the vertebral central nervous system. Antibodies to it, are found in a number of autoimmune neurological conditions such as stiff person syndrome and autoimmune epilepsy and encephalitis, but have no specific syndrome associations unlike GAD2. Expression of GAD1 has been implicated in the pathophysiology of schizophrenia, in working memory impairment and dyskinesia. The GAD25 isoform is expressed outside the nervous system in pancreatic islets, testis and adrenal cortex.
GAD1 mutation can cause spastic quadriplegic cerebral palsy 1 (CPSQ1, OMIM:603513) with symmetrical, non-progressive spasticity, developmental delay and sometimes epilepsy. Other mutations have been weakly associated with cleft palate.
Glutamate decarboxylases catalyse the breakdown of GABA with pyridoxal 5'-phosphate as a cofactor:
L-glutamate -> 4-aminobutanoate + CO2.
- ↑ Gresa-Arribas N, Ariño H, Martínez-Hernández E, Petit-Pedrol M, Sabater L, Saiz A, Dalmau J, Graus F. Antibodies to inhibitory synaptic proteins in neurological syndromes associated with glutamic acid decarboxylase autoimmunity. PloS one. 2015; 10(3):e0121364.(Epub) (Link to article – subscription may be required.)
- ↑ Mitchell AC, Jiang Y, Peter C, Akbarian S. Transcriptional regulation of GAD1 GABA synthesis gene in the prefrontal cortex of subjects with schizophrenia. Schizophrenia research. 2015 Sep; 167(1-3):28-34.(Link to article – subscription may be required.)
- ↑ Lett TA, Kennedy JL, Radhu N, Dominguez LG, Chakravarty MM, Nazeri A, Farzan F, Walter H, Heinz A, Mulsant BH, Daskalakis ZJ, Voineskos AN. Prefrontal White Matter Structure Mediates the Influence of GAD1 on Working Memory. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2016 Jan 29.(Epub ahead of print) (Link to article – subscription may be required.)
- ↑ Zhang K, Chammas C, Soghomonian JJ. Loss of glutamic acid decarboxylase (Gad67) in striatal neurons expressing the Drdr1a dopamine receptor prevents L-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned mice. Neuroscience. 2015 Sep 10; 303:586-94.(Link to article – subscription may be required.)