Brain cells continually extract material from the fluid around them, including nutrients, signaling molecules, and fragments of their own external surfaces. This process, called endocytosis, supports learning, memory, and routine maintenance of neurons.
Penn State researchers have now identified a previously unrecognized structure that may control much of this activity. The structure is a network located just beneath the surface of neurons and is known as the membrane-associated periodic skeleton, or MPS.
A hidden guardian within neurons
In findings published in Scientific advancesThe team showed that MPS acts as a physical gatekeeper for almost all major types of endocytosis. Built from repeating rings of proteins, the structure was already known to help neurons retain their shape. The new results indicate that it also plays a much more active role in controlling where and when substances enter the cell.
“For many, many years we have been trying to understand this molecular mechanism, what kind of machinery will help facilitate this process, because it is connected to neurodegenerative diseases,” said Ruobo Zhou, assistant professor of chemistry, biochemistry and molecular biology, and of biomedical engineering, at Penn State and corresponding author of the study. “When endocytosis (this uptake and regulation of nutrients) goes wrong, there is an aggregation of proteins that build up in the brain, which is the hallmark of neurodegenerative diseases such as Alzheimer’s and Parkinson’s.”
Zhou helped discover MPS in 2013 while working as a postdoctoral researcher on a team at Harvard. At the time, scientists believed the structure served primarily as a passive internal support system. In the new study, Zhou and his colleagues used super-resolution imaging on neurons cultured in the lab and found that MPS behaves more like a controller of cellular trafficking, regulating all major forms of endocytosis.
Observing cellular uptake at the nanoscale
The researchers relied on advanced super-resolution microscopy, which can reveal nanoscale structures, approximately 10,000 times smaller than the thickness of a human hair. They studied neurons grown in Petri dishes and caused select proteins to form inside the cells so they could track them.
The scientists then exposed the neurons to different molecules and watched as the cells absorbed them while the MPS remained intact. They also altered the structure by damaging or protecting specific sections, allowing them to see how the neurons responded when the network changed.
When MPS was interrupted, the neurons began to absorb material much faster. This indicated that the network normally slows down the process and prevents excessive absorption.
The researchers also found that the structure can contribute to its own decomposition. Faster endocytosis weakened the network and triggered a positive feedback loop. Increased uptake activated molecular signals that directed proteins inside neurons to sever sections of the skeleton. That opened up additional entry points and allowed even more nutrients and protein to enter.
“We found that this membrane skeleton actively regulates the nutrient absorption process of neurons,” Zhou said. “You can think of it as a gatekeeper, protecting this physical barrier from allowing nutrient absorption to occur. When a neuron needs to absorb a specific nutrient, this gatekeeper will open the gates and let it in.”
Zhou explained that this flexibility may allow neurons to increase their activity when they need to respond quickly. However, the same mechanism could become harmful if it is no longer properly controlled.
A possible link to Alzheimer’s disease
To investigate that possibility, the researchers created cellular experiments that resembled the early stages of Alzheimer’s disease. They caused neurons to produce higher levels of amyloid precursor protein (APP), a key marker associated with the disease.
Weakening MPS caused neurons to take up APP more quickly. After entering cells, APP was cleaved into amyloid B42, a toxic fragment strongly associated with Alzheimer’s disease. Neurons with damaged MPS accumulated increasing amounts of this harmful molecule and showed more markers of cell death.
“We created a model that closely resembles Alzheimer’s disease and found that in some neurons aged or under pathological conditions, endocytosis of toxic proteins increased, causing stressful conditions that ultimately led to the death of neurons,” said Jinyu Fei, a graduate student in the chemistry department at Penn State’s Eberly College of Sciences and lead author of the study.
A possible new treatment target
The results suggest that MPS may act as a protective barrier in neurons by slowing the uptake of APP and limiting the accumulation of toxic molecules. Because the structure is known to deteriorate during aging and neurodegenerative diseases, its degradation could push neurons into a damaging cycle involving increased amyloid production, further structural weakening, and eventually cell death.
The researchers said protecting or stabilizing this network may offer a new way to slow neurodegeneration.
“We believe this could open the door to future therapies, such as a target protein for the treatment of neurodegenerative diseases,” Fei said. “Preserving or stabilizing MPS could offer a way to slow the early, hidden cellular changes that precede Alzheimer’s symptoms.”
Other authors of the paper are Yuanmin Zheng, a doctoral candidate in biomedical engineering; Caden LaLonde, fourth-year undergraduate student majoring in biochemistry and molecular biology; and Yuan Tao, a graduate student at Penn State’s Huck Institutes of Life Sciences.
The National Institutes of Health funded this work.