Cognitive tasks, such as learning and memory, require rapid changes to proteins at synapses, such as protein synthesis, degradation, and trafficking. How protein post-translational modifications regulate synaptic site targeting remains an open question.
In a new study published in Science Advances titled “Cypin regulates K63-linked polyubiquitination to shape synaptic content,” researchers from Rutgers University report that a brain protein known to support neuron communication, named cypin, modulates synaptic content via K63-polyubiquitination (polyUb) in a mouse model. The results provide insight into the basic mechanism of neuronal signaling for therapeutic applications.
“Our research indicates that developing treatments or therapies that specifically focus on the protein cypin may help improve the connections between brain cells, enhancing memory and thinking abilities,” said Bonnie Firestein, PhD, a distinguished professor in the Department of Cell Biology and Neuroscience at Rutgers and corresponding author of the study.
Modifying a protein with ubiquitin is commonly known to regulate degradation by marking proteins for breakdown by the proteasome. The authors examined changes in two different types of ubiquitination linkages, K48 and K63, and identified that K63-polyUB played an integral role in modulating proteins in neurons in both in vitro and in vivo settings.
K63-polyUb linkages have mostly been studied in the context of cancer. While K63-polyUB has been documented to participate in the DNA damage response, control protein kinase activation, mediate protein trafficking, and regulate endocytosis and autophagy, its function in neurons has been poorly understood.
Regulation of K63-polyUB by cypin influenced pre- and postsynaptic protein abundance in both developing neurons and in vivo in the adult mouse. Mechanistically, the authors found that cypin overexpression alters the levels of proteasome subunits in developing neurons by regulating UBE4A, a polyubiquitination enzyme. Cypin overexpression decreased proteasome activity by binding to the β7 proteasome subunit. Additionally, proteome subunits in neurons and proteasomal composition at synapses were altered in vitro and in vivo, respectively.
When analyzing synapse plasticity, or the ability of synapses to strengthen or weaken over time, up-regulation of cypin protein expression in vivo significantly increased the levels of postsynaptic density protein 95 (PSD-95), a crucial scaffolding protein found in excitatory synapses, and subunits of glutamate receptors, a family of proteins known to mediate excitatory neurotransmission. These plasticity insights can be applied to counteract the synaptic dysfunction seen in neurodegenerative diseases and brain injuries.
“Even though this study is what we call ‘basic research,’ it eventually can be applied in practical, clinical settings. These findings suggest that cypin could be used to develop treatments for neurodegenerative and neurocognitive diseases, as well as brain injuries,” said Firestein.
In this vein, the Firestein lab is also investigating cypin as a therapeutic target for spinal cord injury (SCI). Researchers are currently evaluating whether activating cypin will improve the morphology and electrophysiology of spinal cord motor neurons following SCI to recover motor function.
The post Synaptic Plasticity Regulated by Protein Modifications Offer Path for Brain Therapeutics appeared first on GEN – Genetic Engineering and Biotechnology News.
