SAPAP Scaffold Proteins: From Synaptic Function to Neuropsychiatric Disorders

Abstract

Excitatory (glutamatergic) synaptic transmission underlies many aspects of brain activity and the genesis of normal human behavior. The postsynaptic scaffolding proteins SAP90/PSD-95-associated proteins (SAPAPs), which are abundant components of the postsynaptic density (PSD) at excitatory synapses, play critical roles in synaptic structure, formation, development, plasticity, and signaling. The convergence of human genetic data with recent in vitro and in vivo animal model data indicates that mutations in the genes encoding SAPAP1-4 are associated with neurological and psychiatric disorders, and that dysfunction of SAPAP scaffolding proteins may contribute to the pathogenesis of various neuropsychiatric disorders, such as schizophrenia, autism spectrum disorders, obsessive compulsive disorders, Alzheimer's disease, and bipolar disorder. Here, we review recent major genetic, epigenetic, molecular, behavioral, electrophysiological, and circuitry studies that have advanced our knowledge by clarifying the roles of SAPAP proteins at the synapses, providing new insights into the mechanistic links to neurodevelopmental and neuropsychiatric disorders.

Keywords: SAPAP/DLGAP/GKAP; animal model; cognitive dysfunction; excitatory synapse; neuropsychiatric disorders; postsynaptic scaffolding protein.

Figure 1

Structure and domains of SAPAP proteins: (A) Amino acid sequence alignment of SAPAPs—SAPAP1 isoform a: 992 amino acids (NP_808307.2); SAPAP2 isoform a: 1059 amino acids (NP_766498.2); SAPAP3: 977 amino acids (NP_001289010.1); SAPAP4 isoform a: 992 amino acids (NP_666240.4). The alignment was generated and visualized using Jalview 2.11.2.0. The potential interacting domains are marked with black lines. (B) Only a subset of known binding partners is shown.

Figure 2

Potential roles of SAPAPs in synaptic function and the pathogenesis of neuropsychiatric disorders. Hypothesized mechanisms of SAPAPs for the molecular signaling underlying OCD, ASD, Fragile X Syndrome, AD and other cognitive disorders are summarized in the figure. AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor; NMDAR, N-methyl-D-aspartic acid receptor; KCh, Shaker-type K⁺ channels; SAPAP, SAP90/PSD-95-associated protein; mGluR1/5, Group I metabotropic glutamate receptors; CaMKII, Calcium/calmodulin-dependent protein kinase II; PKC, Protein kinase C; SynGAP, Synaptic GTPase Activating Protein; nNOS, Neural Nitric Oxide Synthase; S-SCAM, synaptic scaffolding molecule; nArgBP2, Neural Abelson-related gene-binding protein 2; CBL, E3 ubiquitin ligase casitas B-lineage lymphoma; ABL, tyrosine kinase; PYK2, proline-rich tyrosine kinase 2; APP, amyloid precursor protein; P, phosphorylation; FMRP, fragile X mental retardation protein; TRIM3, Tripartite motif-containing 3; Ub, ubiquitin; DLC, dynein light-chain; CDK5, cyclin-dependent kinase 5; TRAP, transmembrane AMPAR regulatory protein.