New insights into protein recycling pathways shed light on how the brain forms memories
University of Michigan researchers have uncovered new details in the complex process that allows neurons to build and strengthen their signaling network. The findings, published in the Journal of Cell Biology, elucidate a cellular mechanism that is central to the brain’s ability to learn and form memories.
“Forming a new memory is all about the connections between neurons that let the neurons influence each other,” says cell biologist Lois Weisman, Ph.D., a research professor at the U-M Life Sciences Institute and a co-senior author of the new study. “But it’s a very complicated process, and there is still so much about how this happens that is unknown.”
Learning and memory formation rely on a mechanism called long-term potentiation, which is the increasing strength of connections between neurons. These connections, or synapses, require the right balance of proteins on the surface of the neuron to send or receive signals. The cell has built-in mechanisms to sense its environment and then adjust the proteins available at the cell surface in response, using recycling pathways that pull proteins into the cell when they’re not needed and return them to the surface when they are.
“We have known for some time that changes in the protein composition of synaptic connections are key for memory encoding, but the mechanism that coordinates delivery of new proteins through different pathways has been unclear,” says co-senior author Michael Sutton, Ph.D., research professor in the Michigan Neuroscience Institute and professor of molecular and integrative physiology in the Medical School.
To date, two recycling pathways have been identified as crucial for maintaining the right protein supply at synaptic sites in mammals: the SNX27 (or sorting nexin family member 27) pathway and the SNX17 pathway, whose role in synapses was only recently determined by research spearheaded by Pilar Rivero-Ríos, Ph.D., a cell biologist in Weiman’s lab.
In their latest study, Rivero-Ríos, Weisman, Sutton and their colleagues revealed that both pathways are required for long-term potentiation, and they work in parallel to maintain distinct sets of proteins at synaptic sites.
“If you think about recycling glass and plastic, those are both required for a comprehensive recycling program, but they are very different processes and neither process can handle the other material,” explains Rivero-Ríos, Ph.D., who led the study. “The same is true for these two pathways: You need both, and neither can substitute for the other.”
Working with cultured mammalian neurons, the team also discovered that both pathways are initiated by the same molecule within the cell: a small signaling molecule called PI(3)P (short for phosphatidylinositol 3-phosphate). When the long-term potentiation process begins, the cell boosts its production of PI(3)P, which then recruits both the SNX27 and the SNX17 pathways to synaptic sites. Blocking PI(3)P production in the cells decreased protein recycling to the cell surface and blocked long-term potentiation.
We now have greater mechanistic insight into the cell biology of long-term potentiation, a process we know is disrupted in neurodegenerative disorders.
Rivero-Ríos believes that alterations in these two protein recycling pathways could be connected to neurodegeneration. Samples from both human patients and mouse models of Alzheimer’s disease, for example, have shown reduced levels of PI(3)P.
“We now have greater mechanistic insight into the cell biology of long-term potentiation, a process we know is disrupted in neurodegenerative disorders,” she says. “We still have many questions to answer, but our findings open the possibility of manipulating these pathways as a potential therapeutic strategy.”
Go to Article
“PI(3)P coordinates SNX17- and SNX27-dependent protein recycling for long-term synaptic plasticity," Journal of Cell Biology. DOI: 10.1083/jcb.202411198