Disks large homolog 3

Disks Large Homolog 3 (DLG3) is a synaptic scaffolding protein required for learning, primarily through its role in synaptic plasticity following NMDA receptor signaling (UniProt: Q92796). The protein functions as a membrane-associated guanylate kinase, anchoring signaling complexes at the postsynaptic density.

DLG3 is an X-linked gene associated with intellectual developmental disorder, X-linked 90 (XLID90), a non-syndromic form of X-linked intellectual disability characterized by impaired cognitive and adaptive functioning (UniProt: Q92796). Its involvement in synaptic plasticity suggests broader relevance to cognitive processes.

In Alzheimer's disease, DLG3 is significantly downregulated in post-mortem AD brain tissue compared to age-matched controls (Chaparral AD proteomics). The protein shows a mean log2 fold-change of −0.78 across synaptic subcellular fractions in TMT-labeled quantitative proteomics, indicating reduced synaptic scaffolding capacity. This downregulation may contribute to the synaptic dysfunction and cognitive decline characteristic of AD.