Neurodevelopmental Disorders Associated with PSD-95 and Its Interaction Partners

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• The postsynaptic density (PSD) is crucial for synaptic function, with PSD-95 scaffolding key components.
• Variants in DLG4 (encoding PSD-95) are linked to neurodevelopmental disorders like intellectual disability and epilepsy.
• Similar phenotypes arise from variants in PSD-95 interaction partners, suggesting indirect pathogenic mechanisms.

Purpose of the Study:

• To review transmembrane interaction partners of PSD-95.
• To examine their association with neurodevelopmental disorders.
• To elucidate the indirect role of DLG4 variants via interaction partners.

Main Methods:

• Literature review of PSD-95 and its interaction partners.
• Analysis of structural changes from DLG4 missense variants.
• Assessment of disrupted protein-protein interactions.

Main Results:

• DLG4 variants may indirectly cause pathology by altering PSD-95 interactions.
• Interaction partners of PSD-95 are implicated in similar neurodevelopmental phenotypes.
• Structural changes in PSD-95 can disrupt these crucial interactions.

Conclusions:

• The pathological effects of DLG4 variants are partly mediated through interaction partners.
• Understanding these interactions is key to elucidating PSD-95 deficiency mechanisms.
• This review provides a framework for future functional studies and therapeutic strategies.