Gephyrin

Gephyrin (GPHN) is a multifunctional protein with dual roles in synaptic organization and cofactor biosynthesis (UniProt: Q9NQX3). At inhibitory synapses, it serves as a scaffolding molecule that anchors glycine receptors to microtubules and clusters GABA type A receptors, thereby organizing the structural foundation of inhibitory neurotransmission. The protein also possesses catalytic activity in molybdenum cofactor biosynthesis, catalyzing adenylation of molybdopterin and insertion of molybdate into this modified substrate.

Gephyrin is essential for synaptic inhibition and neuronal function. Genetic mutations cause molybdenum cofactor deficiency type C (MOCODC), a severe autosomal recessive metabolic disorder presenting with early-onset seizures, psychomotor retardation, and poor feeding (UniProt: Q9NQX3). The protein's role in organizing inhibitory synapses suggests broader relevance to neurological homeostasis beyond its cofactor function.

In Alzheimer's disease, gephyrin is significantly downregulated in post-mortem brain tissue compared to age-matched controls (mean log2FC: −0.67) across multiple subcellular fractions in TMT-labeled quantitative proteomics (Chaparral AD proteomics). This reduction may reflect disruption of inhibitory synaptic integrity, a feature increasingly recognized in AD pathology.