Pin1 is and enzyme that is very important when it comes to synaptic plasticity, because it regulates the stability of PSD-95, which is a key building protein in excitatory synapses. The research article and in-class lecture, both by Jary Delgado, demonstrate how Pin1 binding to phosphorylated PSD-95 reduces its palmitoylation, which destabilizes PSD-95 at synapses, leading to fewer excitatory synapses. This mechanism directly influences how synapses are remade and changed, which is critical for learning and memory. Similarly, the Nature Communications article highlights how NMDAR-dependent long-term depression triggers autophagy-mediated degradation of PSD-95, strengthening the theory that PSD-95 levels are regulated during synaptic remodeling. Both sources suggest that PSD-95 is a key target in activity-dependent synaptic changes, highlighting it as a central component for learning and memory.
Beyond basic synaptic function, these findings from both sources have wide implications for neurological disorders linked to synaptic instability. The deterioration of PSD-95 in long-term depression as described in the Nature Communications article, aligns with the findings in the article by Jary Delgado. If PSD-95 homeostasis disruptions help cause synaptic weakening, this could be a link to overall cognitive decline in disorders like AD and Dementia. Additionally, since both palmitoylation and autophagy (cell death) influence PSD-95 stability, future studies could be done to research how these pathways interact and whether malfunction is an underlying factor in synapse loss.
Understanding how both Pin1 works and how PSD-95 stability is regulated provides interesting opportunities for innovation when it comes to things like neurological therapies. If targeted regulation of Pin1 activity can restore synaptic function, that could lead to new treatments for synaptic dysfunction in diseases and general aging. Furthermore, both of these studies show the balance between synaptic strengthening and weakening, which prompts further research into how we can fine-tune synaptic plasticity. By combining research into molecular function and research into clinical implications, many groundbreaking treatments and therapies could be discovered that would greatly improve cognitive and neurodegenerative diseases.
References
Delgado, Jary Y., et al. "Pin1 Binding to Phosphorylated PSD-95 Regulates the Number of Functional Excitatory Synapses." Frontiers in Molecular Neuroscience, vol. 13, 13 mar. 2020, https://doi.org/10.3389/fnmol.2020.00010. Accessed 28 Feb. 2025.
Compans, Benjamin, et al. "NDMMAR-Dependent Long-Term Depression Is Associated with Increased Short Term Plasticity through Autophagy Mediated Loss of PSD-95." Nature Communications, vol. 12, no. 1, 14 May 2021, p. 2849, pubmed.ncbi.nlm.nih.gov/33990590/,https://doi.org/10.1038/s41467-021-23133-9 Accessed 28 Feb. 2025
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