What Impact Does a Single Phosphorylation-Dependent Interaction Between Pin1 and PSD-95 Have on the Stability of Synapses and Their Potential Role in the Early Degeneration of Synapses in Neurodegenerative Disorders?

Dr. Jary Y. Delgado is a neuroscientist who has made great strides in our understanding of the ways molecular mechanisms regulate excitement at excitatory synapses in the hippocampus. The small, post-translational modifications studied in our class demonstrated that these types of changes can have a dramatic impact on synaptic stability and plasticity. Dr. Delgado's studies demonstrate that molecular variations at the nanometre scale are vital in determining if a synapse persists, not just defining or describing larger brain regions or overall activity levels. In addition to the investigation of Pin1 modulation of PSD-95, the role of Phosphorylation-dependent Pin1 is also significant in the modulation and regulation of the stability of PSD-95, which is the most abundant and important scaffolding protein found in excitatory synapses. 

According to the study done by Delgado in 2020, phospho-PSD-95 has an interaction with the phospho-S/T/K motif found within the palmitoylation sites at threonine 19 and serine 25, thus showing the role played by Pin1 in the modulation and regulation of the palmitoylation of PSD-95. Palmitoylation is an essential lipid modification for the proper anchoring of PSD-95-BS to postsynaptic membranes to promote stability in excitatory synapses. In turn, when Pin1 binds to phospho-PSD-95, this prevents the continuous palmitoylation of the phospho-PSD-95 and reduces clustering of phosphorylated PSD95 in dendritic spines, which in turn diminishes the total number of functionally active excitatory synapses (Delgado et al., 2020). The fact that the remaining intact excitatory synapses of an individual's brain continue to exhibit synaptic activity and do not exhibit lower rates of synaptic activity is indicative of how Pin1 can regulate overall levels of synapse formation, but does not impact the functioning of an individual synapse. Pin1 overexpression was observed to correlate with lower density of dendritic spines, whereas the knockdown of Pin1 led to a higher degree of spine density, thus confirming that Pin1 negatively modulates the stability of individual synapses (Delgado et al., 2020). As a result, we conclude that Pin1 serves as a principal cellular mechanism through which phosphorylation and hence, synaptic structural & functional alteration occur. 

Alzheimer’s disease is associated with a reduction in synapses, one of the strongest predictors of cognitive decline from neurodegenerative diseases. A recent study conducted at Stanford University used mouse models of Alzheimer’s to investigate some of the earliest changes in synapses that occur with the disease. The researchers found that synapses begin to destabilize prior to widespread cell death (Taddei and Duff et al., 2025). The authors also stated that abnormal phosphorylation state and disrupted lipid modifications of the postsynaptic scaffolding proteins contribute to the early synaptic vulnerability. Although the study did not directly measure Pin1, the data are highly consistent with the findings of Delgado et al., and together, they demonstrate that post-translational modification of synaptic proteins determines the future stability or loss of the synapses (Taddei and Duff et al., 2025).  

Alzheimer’s Disease has been associated with amyloid plaques/tangles, but cognitive decline/functional impairment is most closely related to synaptic loss versus just the amount of plaque. The similarity between Delgado et al’s finding & that of the 2025 study suggests that pathways that are normal for synaptic plasticity may become dysregulated during disease. For example, this could be represented by the fact that if the level of regulation of the stability of the protein PSD-95 is typically controlled by proteins such as Pin1, then the disruption of this type of protein could lead to higher rates of pathological loss in the synapses than expected. However, this leads to the question of whether therapeutic approaches to the regulation of the pathways of phosphorylation and/or palmitoylation could potentially play a role in the maintenance of synapses during the process of aging and/or neurodegenerative changes. 

Modulation of enhancing and decreasing synaptic connections plays an important role in the regulation of synaptic plasticity. Pin1 appears to have an important role in determining how much of the synaptic scaffolding protein PSD-95 is retained and stabilised at synapses. The normal regulation of PSD-95 at the synapse should allow for healthy activities such as long-term depression to occur, however, any dysregulation could put individuals at risk for developing a disease. The research of Dr. Delgado establishes a direct relationship between a specific molecular interaction and multiple functional characteristics of a synapse, including spine density, receptor mobility, and overall synapse quantity(Delgado et al. 2020). The connection between the work of Dr. Delgado and studies related to the current state of Alzheimer’s disease demonstrates that research in molecular neuroscience is relevant to both basic science and answering current public health problems. Researchers can begin creating strategies that preserve cognitive ability prior to serious cognitive decline by understanding how synapses are formed and lost at the molecular level. 

References 

Delgado , Jary, et al. Pin1 Binding to Phosphorylated PSD-95 Regulates the Number of 

Functional Excitatory Synapses, 13 Mar. 2020, pubmed.ncbi.nlm.nih.gov/32231520/. 

Taddei, Raquel, and Karen Duff. Synapse Vulnerability and Resilience Underlying Alzheimer’s 

Disease, 31 Jan. 2025, www.thelancet.com/journals/ebiom/article/PIIS2352-3964(25)00001-5/fulltext.