Brain cells continually extract substances such as nutrients, signaling molecules, and fragments of their own outer surfaces from the surrounding body fluids. This process, called endocytosis, supports learning, memory, and the daily maintenance of neurons.
Researchers at Penn State University have identified a previously unrecognized structure that may control much of this activity. This structure is a lattice located just below the surface of neurons and is known as the membrane-associated periodic skeleton (MPS).
Hidden gatekeepers within neurons
According to the survey results published in scientific progressthe research team showed that MPS acts as a physical gatekeeper for nearly all major types of endocytosis. This structure, built from repeating rings of proteins, was already known to help neurons maintain their shape. The new results show that it also plays a more active role by controlling where and when substances enter cells.
“We’ve been trying to understand this molecular mechanism for years, and what kind of machinery might help facilitate this process as it’s associated with neurodegenerative diseases,” said Luobo Zhou, assistant professor of chemistry, biochemistry, molecular biology, and biomedical engineering at Penn State and corresponding author of the study. “When endocytosis (nutrient uptake and regulation) goes wrong, protein aggregates build up in the brain, a hallmark of neurodegenerative diseases such as Alzheimer’s and Parkinson’s.”
Chou contributed to the discovery of MPS in 2013 while working as a postdoctoral researcher on a team at Harvard University. At the time, scientists believed that this structure primarily served as a passive internal support system. In the new study, Zhou and colleagues used super-resolution imaging on neurons grown in the lab and found that the MPS acts like a cell traffic controller, controlling all major forms of endocytosis.
Observing cellular uptake at the nanoscale
The researchers used advanced super-resolution microscopy that can reveal structures at the nanoscale (about 1/10,000 times the thickness of a human hair). They studied neurons grown in Petri dishes and allowed selected proteins to form inside the cells so they could track them.
The scientists then exposed the neurons to different molecules and observed how the cells absorbed them while the MPS remained intact. They also modified the structure by damaging or protecting specific sections, allowing them to observe how neurons react when the lattice changes.
Once the MPS was destroyed, the neurons began absorbing material much faster. This indicates that the lattice normally slows down the process and prevents excessive uptake.
The researchers also discovered that this structure can contribute to its own destruction. Faster endocytosis weakened the lattice, triggering a positive feedback loop. The increased uptake activated molecular signals that told proteins in the neurons to cut off parts of the scaffold. This opens additional entry points, allowing more nutrients and proteins to enter.
“We discovered that this membrane skeleton actively regulates the nutrient uptake process in neurons,” Zhou said. “You can think of this as a gatekeeper that protects this physical barrier so that nutrient uptake doesn’t occur. If a neuron needs to take in a particular nutrient, this gatekeeper opens the gate and lets the nutrient in.”
Zhou explained that this flexibility may allow neurons to increase their activity when they need to react quickly. However, these same mechanisms can be harmful if they are no longer properly controlled.
Possible association with Alzheimer’s disease
To investigate that possibility, researchers created a cell experiment that resembles the early stages of Alzheimer’s disease. These caused neurons to produce high levels of amyloid precursor protein (APP), a key marker associated with the disease.
Attenuating MPS causes neurons to take up APP more quickly. Once in the cell, APP was cleaved into amyloid B42, a toxic fragment strongly associated with Alzheimer’s disease. MPS-damaged neurons had increased accumulation of this harmful molecule and displayed more cell death markers.
“We created a model that closely resembles Alzheimer’s disease and found that some aging or diseased neurons have increased endocytosis of toxic proteins, which triggers stress conditions and ultimately leads to neuronal death,” said Jinyu Fei, a graduate student in the Department of Chemistry at Penn State’s Eberly College of Science and lead author of the study.
Potential new therapeutic targets
This result suggests that MPS may act as a protective barrier for neurons by slowing APP uptake and limiting the accumulation of toxic molecules. This structure is known to deteriorate with aging and neurodegenerative diseases, and its destruction can put neurons into a damaging cycle with increased amyloid production, further structural weakening, and eventual cell death.
The researchers said protecting or stabilizing this lattice could provide a new way to slow neurodegeneration.
“We think this could open the door to future therapeutics, including protein targets for treating neurodegenerative diseases,” Professor Fay said. “Preserving or stabilizing MPS may provide a way to slow the early hidden cellular changes that precede Alzheimer’s disease symptoms.”
Other authors of the paper are Yuanmin Zheng, a doctoral candidate in biomedical engineering; Caden LaLonde, fourth-year undergraduate majoring in biochemistry and molecular biology. and Yuan Tao, a graduate student at Penn State’s Huck Institute for Life Sciences.
The National Institutes of Health funded this study.
