Neurodevelopmental Disorders Associated with PSD-95 and Its Interaction Partners

Abstract

The postsynaptic density (PSD) is a massive protein complex, critical for synaptic strength and plasticity in excitatory neurons. Here, the scaffolding protein PSD-95 plays a crucial role as it organizes key PSD components essential for synaptic signaling, development, and survival. Recently, variants in DLG4 encoding PSD-95 were found to cause a neurodevelopmental disorder with a variety of clinical features including intellectual disability, developmental delay, and epilepsy. Genetic variants in several of the interaction partners of PSD-95 are associated with similar phenotypes, suggesting that deficient PSD-95 may affect the interaction partners, explaining the overlapping symptoms. Here, we review the transmembrane interaction partners of PSD-95 and their association with neurodevelopmental disorders. We assess how the structural changes induced by DLG4 missense variants may disrupt or alter such protein-protein interactions, and we argue that the pathological effect of DLG4 variants is, at least partly, exerted indirectly through interaction partners of PSD-95. This review presents a direction for functional studies to elucidate the pathogenic mechanism of deficient PSD-95, providing clues for therapeutic strategies.

Keywords: DLG4; clinical genetics; epilepsy; excitatory synapses; glutamate signaling; intellectual disability; postsynaptic density; synaptopathy.

Figure 1

Simplified schematic overview of the major PSD-95 interactions in the postsynaptic density. (A) PSD-95 anchors K_v1 channels, NMDA receptors, and AMPA receptors (through stargazin) to the postsynaptic membrane as they bind the first two PSD-95/Discs large/Zonula occludens 1 (PDZ) domains of PSD-95, whereas neuroligin and ADAM22 bind the third PDZ domain. Amongst others, PSD-95 also binds PTK2B, which is recruited to the NMDAR-PSD-95-complex through binding to PSD-95 SRC homology 3 (SH3) domain, AKAP, which links the NMDAR–PSD-95-complex with signaling enzymes (not shown), and SynGAP, which binds all three PSD-95 PDZ domains. Furthermore, SAPAP binds PSD-95 guanylate kinase-like (GK) domain and actin-binding Shank, forming a scaffolding protein complex, which anchors the actin cytoskeleton to the postsynaptic membrane. Transsynaptic interactions include the neuroligin–neurexin interaction as well as the ADAM22–LGI1–complex. The location of the latter is based on one of the models proposed by Fukata et al. [3]. (B) Representative diagram of the structure of NMDAR, AMPAR, and K_v1 as well as their interaction with PSD-95, which is anchored to the postsynaptic membrane through N-terminal palmitoylation. NMDARs most often comprise two obligate GluN1 subunits (pink) and two GluN2 subunits (purple), although they also exist as triheterotetramers (GluN1–GluN1–GluN2–GluN3; not shown). Various K_v1α-subunits assemble in homo- or heterotetramers to form the K_v1 channels. The most common AMPAR subunit composition includes two GluA1 (orange) and two GluA2 subunits (yellow), although they may also include GluA3 and/or GluA4 subunits. N, N-terminal; C, C-terminal.

Figure 2

PSD-95 missense variants. Schematic (left) and structural (right) model of human PSD-95. The locations of the PDZ1, 2, and 3, SH3, and GK domains as well as the missense variants (p.(Gly177Val), p.(Asp186Val), p.(Gly198Ser), p.(Gly198Arg), p.(Asp332Gly), p.(Arg586Gln), and p.(Thr611Ile)) are indicated. Locations are described according to NP_001308004.1. N, N-terminal; C, C-terminal.