Abstract
Glutamic acid decarboxylase (GAD) is an intracellular enzyme whose physiologic function is the decarboxylation of glutamate to gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter within the central nervous system. GAD antibodies (Ab) have been associated with multiple neurological syndromes, including stiff-person syndrome, cerebellar ataxia, and limbic encephalitis, which are all considered to result from reduced GABAergic transmission. The pathogenic role of GAD Ab is still debated, and some evidence suggests that GAD autoimmunity might primarily be cell-mediated. Diagnosis relies on the detection of high titers of GAD Ab in serum and/or in the detection of GAD Ab in the cerebrospinal fluid. Due to the relative rarity of these syndromes, treatment schemes and predictors of response are poorly defined, highlighting the unmet need for multicentric prospective trials in this population. Here, we reviewed the main clinical characteristics of neurological syndromes associated with GAD Ab, focusing on pathophysiologic mechanisms.
Highlights
Glutamic acid decarboxylase (GAD) is an intracellular enzyme fairly expressed in neurons and insulin-secreting pancreatic β cells, whose physiologic function is the decarboxylation of glutamate to gamma-aminobutyric acid (GABA) [1,2].GAD exists in two isoforms, GAD65 and GAD67, that share a similar structure consisting of an amino-terminal domain, a catalytic domain binding the cofactor pyridoxal 5’-phosphate (PLP), and a carboxy-terminal domain [3]
When synaptic vesicles fusion with the plasma membrane intracellular proteins, mechanism that ensures that GABA synthesis is coupled to its packaging in during
Ab titers might be insufficient to distinguish whether the detection of GAD Ab in serum is in relation with the neurological syndrome or with an underlying T1DM
Summary
Glutamic acid decarboxylase (GAD) is an intracellular enzyme fairly expressed in neurons and insulin-secreting pancreatic β cells, whose physiologic function is the decarboxylation of glutamate to gamma-aminobutyric acid (GABA) [1,2]. Being almost saturated with the PLP cofactor [4], GAD67 is constantly active and ensures the synthesis of basal levelswith of GABA [11]. GAD65 is primarily in the pre-synaptic end of nerve terminals, it active form [4,10], GAD65 allows a rapid and synthesis of when needed. By switching from the inactive to the active beinga an intracellular enzyme, pre-clinical studies have shown that GAD65 is formNotwithstanding [4,10], GAD65 allows rapid and synthesis of GABA able Notwithstanding to associate withbeing the plasma membrane [13]. When synaptic vesicles fusion with the plasma membrane intracellular proteins, mechanism that ensures that GABA synthesis is coupled to its packaging in during.
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