Memory systems serve as foundations of critical cognition; within these systems, vital proteins play key roles at the synaptic level of long-term potentiation and long-term depression. One of the key proteins, the most abundant protein present at the synapse, is postsynaptic density protein 95. PSD-95 allows rapid regulation of synaptic strength derived from neuronal activity; when palmitoylated, PSD-95 acts as an anchor for AMPA receptors, making it a key protein of interest.
Authors Delgado et al. (2020) explored molecular research on PSD-95’s role within excitatory synapses and synaptic plasticity focused on the mechanisms behind erosion of higher cognitive thinking. Dr. Delgado introduced the idea that peptidyl-prolyl isomerase Pin1 plays a role in regulatory function in excitatory synapses. This research aims to provide insight on the molecular basis that led to cancer development, Alzheimer’s, and other neurodegenerative disorders and to potentially aid in intercepting symptoms for patients prone to suffering from these diseases. Delgado and his team found that a peptidyl-prolyl isomerase called PIN1 binds to phosphorylated T19 and S25 within the PSD-95 N-terminus domain, leading to a significant reduction of 70% total PSD-95 palmitoylation. Through extensive research, they came to find that the reduction of PSD-96 palmitoylation capacity significantly reduced amounts of functional synaptic receptors due to decreased stability. The interaction between Pin1 and PSD-95 determines the number of excitatory synapses and the mobility of AMPA receptors, which are crucial for synaptic transmission.
Professor Jaehoon Jeong et al. (2019) also decided to explore the importance of PSD-95, specifically the interaction of PSD-95 with NLGN1, a postsynaptic cell adhesion protein that aids in the formation of stable excitatory synapses. NLGN1 guides neurotransmission by coordinating the alignment of presynaptic release sites to their corresponding postsynaptic receptors, and just like Pin1’s interaction with PSD-95, NLGN1 is linked with the development of Alzheimer’s as well. However, NLGN1’s function as a biomarker for Alzheimer’s is the opposite of Pin1 binding; NLGN1 levels are found to be significantly lowered in patients with AD compared to control patients. The interaction between PSD-95 and NLGN1 is a protein-protein binding mechanism where NLGN1 binds onto PSD-95’s third PDZ domain. Just in the case of Pin1, PSD-95 in this case acts as a scaffolding protein that many other things anchor onto, in this case NLGN1. Dr. Jeong’s findings are significant as they point to links between PSD-95 and NLGN1 to underlying neurodegenerative processes.
Research on the vast variety of functions of PSD-95 is still being studied, and the nature of PSD-95 is mostly unknown. Likely with continued research of important PSD-95 interactions, neuronal circuit models can be formulated. Through this research, neurodegeneration will be identified early on, where preventative medical measures can be taken to curb symptoms before they worsen.
REFERENCES
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. https://doi.org/10.3389/fnmol.2020.00010
Jeong, J., Pandey, S., Li, Y., Badger, J. D., Lu, W., & Roche, K. W. (2019). PSD-95 binding dynamically regulates NLGN1 trafficking and function. Proceedings of the National Academy of Sciences, 116(24), 12035–12044. https://doi.org/10.1073/pnas.1821775116
Camporesi, E., Lashley, T., Gobom, J., Lantero-Rodriguez, J., Hansson, O., Zetterberg, H., Blennow, K., & Becker, B. (2021). Neuroligin-1 in brain and CSF of neurodegenerative disorders: investigation for synaptic biomarkers. Acta Neuropathologica Communications, 9(1). https://doi.org/10.1186/s40478-021-01119-4
No comments:
Post a Comment