Brain cells are constantly swallowing material from the fluid that surrounds them – signaling molecules, nutrients, even pieces of their own surfaces – in a process known as endocytosis that is essential for learning, memory and basic neural upkeep.
Now, new research by Penn State scientists has revealed this vital process may be governed by a previously unknown molecular gatekeeper: a lattice‑like structure just beneath the surface of brain cells, or neurons, called the membrane‑associated periodic skeleton or MPS.
In a study published today (Feb. 11) in the journal Science Advances, the researchers demonstrated that the MPS structure lining nerve cells acts as a physical gatekeeper for nearly every major form of endocytosis. The structure, made of repeating rings of proteins, was previously known for helping neurons maintain their shape. The scientists said they now understand it plays a far more active role by deciding where and when cells can take things in.
“For many, many years we have been trying to understand this molecular mechanism, what kind of machinery will help to facilitate this process, because it’s connected to neurodegenerative diseases,” said Ruobo Zhou, assistant professor of chemistry, of biochemistry and molecular biology, and of biomedical engineering, at Penn State and corresponding author on the study. “When endocytosis – this nutrient uptake and regulation – goes wrong, then there’s protein aggregation that will build up in the brain, which is the hallmark of neurodegenerative diseases such as Alzheimer’s and Parkinson’s.”
As a postdoctoral researcher in 2013, Zhou was part of the Harvard team that first discovered the skeleton structure inside neurons that researchers thought was a passive support structure. Using super-resolution imaging of cultured neurons in this new study, Zhou’s team was able to demonstrate that the MPS is far more active, behaving like a gatekeeper to serve as a kind of cellular traffic control for all major forms of endocytosis.
The team used advanced super‑resolution microscopy, a type of imaging technique that can peer into cells at the nanoscale – about 10,000 times smaller than the thickness of a human hair – to study neurons grown in petri dishes in the lab. They made specific proteins grow inside the neurons, so they could track them, and fed the neurons different molecules to study the uptake process when the MPS was functioning in its normal state. Then, they manipulated the MPS by breaking or protecting parts of the structure to see what the brain cell did in response.
When the researchers disrupted the MPS, neurons began taking in material far more quickly, suggesting the lattice normally acts as a brake. But the most striking discovery was that the structure will also break itself, the researchers said. They found that accelerated endocytosis could weaken the lattice and set off a positive feedback loop: Increased cellular uptake activated molecular signals that told proteins inside the brain cells to chop up parts of its skeleton, opening more doors and accelerating further nutrient and protein uptake.
“We discovered that this membrane skeleton is actively regulating the nutrient uptake process of neurons,” Zhou said. “You can think of it as a gatekeeper, guarding this physical barrier to not allow nutrient uptake to happen. When a neuron needs to take in a specific nutrient, this gatekeeper will open the gates and let it in.”
This dynamic may help neurons ramp up activity when rapid responses are needed, Zhou explained, but it could also have a downside.
The researchers designed cellular experiments to mimic the early stages of Alzheimer’s disease by making neurons produce extra amyloid precursor protein (APP), a key marker of the disease. They found that degrading the MPS sped up the intake of APP. Once inside neurons, APP clipped into amyloid‑B42, a neurotoxic fragment strongly linked to Alzheimer’s disease. With the MPS weakened, neurons accumulated more and more of this harmful molecule and showed higher levels of markers for cell death.
“We created a model which is very much like Alzheimer’s disease and found that in some aging neurons, or neurons under pathologic conditions, the endocytosis of toxic proteins was enhanced, which caused stressing conditions, ultimately leading to neuron deaths,” said Jinyu Fei, a graduate student in the chemistry department in Penn State’s Eberly College of Science and lead author on the study.
The team’s findings suggest that the MPS may serve as a neuroprotective barrier, slowing APP uptake and helping keep toxic molecules in check. Its breakdown, already observed in aging and neurodegenerative disease, could tip neurons into a destructive cycle of increased amyloid production and structural decay. Preserving this lattice, the researchers suggested, could become a new strategy for slowing neurodegeneration.
“We think this could open the door for future therapies such as a protein target for neurodegenerative disease treatment,” Fei said. “Preserving or stabilizing the MPS might offer a way to slow the early, hidden cellular changes that precede Alzheimer’s symptoms.”
Other authors on the paper are Yuanmin Zheng, doctoral candidate in biomedical engineering; Caden LaLonde, fourth-year undergraduate student majoring in biochemistry and molecular biology; and Yuan Tao, graduate student at Penn State’s Huck Institutes of Life Sciences.
The National Institutes of Health funded this work.