Scaffold proteins play a vital role in neurons by organizing and stabilizing key signaling components at synapses to ensure efficient communication between cells. They act as molecular platforms most commonly found in the postsynaptic density (PSD) of excitatory synapses where they help organize neurotransmitter receptors, enzymes, and other structural proteins to regulate synaptic strength and plasticity. One well-known scaffold protein, postsynaptic density protein 95 (PSD-95) is very influential in maintaining excitatory synapses by anchoring glutamate receptors AMPA and NMDA. These proteins influence learning, memory and brain function, seen in the forms of long-term depression (LTD), where synaptic strength is weakened over time and decreases our likelihood of recalling certain memories; and long-term potentiation (LTP), which is the opposite of LTP where synaptic connections are strengthened---leading to memory formation. Studying scaffold proteins in neurons is very important because their dysfunction is often linked to neurological disorders such as Alzheimer's disease. The next section will highlight Dr. Jary Delagado's research done on examining the roles PSD-95 and Pin1 play regarding LTD.
In Dr. Delgado's research, he and his team investigated how the interaction between Pin1 and phosphorylated PSD-95 influences the number of functional excitatory synapses. As mentioned before, PSD-95 is an important scaffold protein, and Pin1, which is an enzyme that selectively binds to phosphorylated PSD-95, potentially modulating its function in synaptic organization. The researchers conducted molecular and electrophysiological experiments to determine how Pin1-PSD-95 interactions impact synaptic strength. Their findings indicated that Pin1 binding to phosphorylated PSD-95 significantly regulates the number of functional excitatory synapses. And more specifically, disrupting this interaction resulted in altered synaptic density and changes in transmission efficiency. Overall, these results suggest Pin1 does play a crucial in the post-translational regulation of PSD-95, affecting synaptic plasticity and neuronal communication.
A recent study done by researchers at Johns Hopkins Medicine revealed a new function to the SYNGAP1 gene, which is a DNA sequence important in regulating memory and learning in mammals. Traditionally, this gene was believed to encode a protein (SynGAP) that influenced synaptic strength through chemical reactions. However, experiments in mice revealed that the SynGAP protein also acts as a scaffold protein, in how it organizes synaptic components and modulates synaptic plasticity. The experiments revealed that SynGAP during synaptic plasticity becomes disconnected from PSD-95, which allowed for neurotransmitter receptors to bind, increasing the synaptic strength and transmission. This discovery of an additional mechanism to this protein is important because it has been discovered many children with SynGAP mutations have roughly half the number of normal SynGAP proteins in the synapse. With fewer of these proteins in the synapse, a drastic increase in brain cell activity occurs with the binding of more AMPA receptors, which can lead to epileptic seizures. Further understanding the mechanisms behind these proteins can help lead to therapies for those with dysfunction or mutations in them, in hope to prevent neurological diseases.
To conclude, scaffold proteins such as PSD-95 and SynGAP are very important for organizing synapses and regulating the brain functions of memory formation, and memory decay. Research done by Dr. Delgado, and researchers at Johns Hopkins Medicine, have discovered important mechanisms for these scaffold proteins in relation to synaptic plasticity. By identifying how these proteins function and interact with other complexes, researchers can begin to use this understanding of how they are regulated to create new therapeutic approaches in hopes of treating neurological diseases.
References:
Dr. Delgado's paper: https://pubmed.ncbi.nlm.nih.gov/32231520/
Johns Hopkins paper: https://www.sciencedaily.com/releases/2024/02/240229182901.htm
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