Alzheimer's Disease and Posttranslational Modifications of PSD-95

 

Long Term Depression (LTD) is much less understood than its counterpart, Long Term Potentiation (LTP). However, better understanding the molecular mechanisms to LTD is vital as dysregulation in LTD is frequently implicated in neurological disorders. NMDAR Dependent LTD (NMDAR-LTD) is one of mechanisms in which LTD can occur and involves calcium influx through NMDAR receptors activating pathways that result in the endocytosis of AMPA receptors Dr. Delgado discussed how posttranslational modification of PSD-95 can regulate NMDAR-LTD. PSD-95 is a scaffolding protein that is very abundant in glutamatergic synapses. It works to support NMDA receptors in the postsynaptic membrane through its structural role. PSD-95 can undergo a wide variety of posttranslational modifications such as isomerization, phosphorylation, ubiquitination, and palmitoylation (Alkaas et al., 2025). These posttranslational modifications of PSD-95 have been shown to impact NMDAR-LTD.  

              Dr. Jary Delgado has been conducting research on how posttranslational modifications of PSD-95 can impact AMPAR endocytosis and LTD by altering PSD-95 stability. He found that Pin1, an isomerase that binds to phosphorylated residues on PSD-95, regulates palmitoylation (Delgado et al., 2020). Palmitoylation is the covalent linkage of a 16-carbon fatty acid, palmitic acid, to a cysteine residue (Alkaas et al., 2025). Decreases in palmitoylation of PSD-95 result in a decrease in functional excitatory synapses; Delgado and his colleagues found that phosphorylation of T19/S25 on PSD-95 recruits the isomerase Pin1 which leads to a decrease in PSD-95 palmitoylation (2020).

              This made me think about how Pin1 and PSD-95 might be related to neurodegenerative disease as they are important for regulation of  functional synapses. Amyloid ß is one of the most well-established biomarkers of Alzheimer’s Disease, elevated Aß levels can lead to the loss of synapses (Dore et al., 2021). Dore and her colleagues found that inhibition of enzymes responsible for PSD-95 depalmitoylation  rescued Aß synaptic weaking, leading them to believe that PSD-95 palmitoylation is protective against synaptic weakening caused by Aß. This makes palmitoylation of PSD-95 a potential therapeutic target for treating Alzheimer’s Disease. 

              Taking this finding alongside the findings of Delgado and his colleagues may point towards excessive Pin1 activity as a potential mechanism behind Alzheimer’s Disease as Pin1 function is associated with decreases in PSD-95 palmitoylation and PSD-95 palmitoylation was shown to be a protective factor against effects of Aß. Perhaps pathways involving Pin1 isomerization should be further studied to evaluate potential therapeutics against Alzheimer’s Disease. Overall, more research involving posttranslational modifications of PSD-95 need to be studied in relation to biomarkers of Alzheimer’s Disease and other neurodegenerative diseases to develop translational research for creating therapeutics against Alzheimer’s Disease.

References

Alkaas, A., Kurup, P., Kanuru, S., Von Rommel, A., Singh, T., Patel, M. J., & Delgado, J. Y. (2025). Synaptic PSD-95 biology: from localization and interactors to N-terminus function. Journal of Neurophysiology, 134(5), 1588–1606. https://doi.org/10.1152/jn.00272.2025

Delgado, J. Y., Nall, D., & Selvin, P. R. (2020). Pin1 Binding to Phosphorylated PSD-95 Regulates the Number of Functional Excitatory Synapses. Frontiers in molecular neuroscience, 13, 10. https://doi.org/10.3389/fnmol.2020.00010

Dore, K., Carrico, Z., Alfonso, S., Marino, M., Koymans, K., Kessels, H. W., Malinow, R. (2021). PSD-95 protects synapses from ß-amyloid. Cell Press, 35, 109194. https://doi.org/10.1016/j.celrep.2021.109194