Penn State scientists have discovered a surprising regulator of brain cell activity, potentially unlocking new avenues for treating neurodegenerative diseases. Published today, February 11, in Science Advances, the research reveals that the membrane-associated periodic skeleton (MPS)—a lattice-like structure beneath neuron surfaces—acts as a “gatekeeper” for endocytosis, the vital process of nutrient uptake essential for learning and memory. Using advanced super-resolution microscopy, the team demonstrated the MPS isn’t a passive support, but actively controls when and where cells take in materials. “For many, many years we have been trying to understand this molecular mechanism…because it’s connected to neurodegenerative diseases,” said Ruobo Zhou, assistant professor at Penn State and lead author. This discovery suggests that malfunctions in the MPS could contribute to the protein aggregation characteristic of Alzheimer’s and Parkinson’s.
MPS Structure Regulates Endocytosis in Neurons
This isn’t merely a structural support, as previously thought, but an active “gatekeeper” dictating when and where neurons take things in. The team utilized advanced super-resolution microscopy, capable of imaging at the nanoscale—roughly 10,000 times smaller than a human hair—to observe neurons grown in laboratory conditions. They tracked specific proteins and monitored nutrient uptake, both with a functioning MPS and when the structure was deliberately altered. Disrupting the MPS led to dramatically increased uptake rates, indicating its normal function is to apply a brake on the process.
Notably, the MPS isn’t static; researchers discovered it can actively break down, initiating a feedback loop where increased endocytosis further weakens the lattice. “We discovered that this membrane skeleton is actively regulating the nutrient uptake process of neurons,” said Ruobo Zhou, assistant professor of chemistry, biochemistry and molecular biology, and biomedical engineering at Penn State. This dynamic regulation has significant implications for diseases like Alzheimer’s.
Experiments mimicking early Alzheimer’s stages revealed that weakening the MPS accelerated the uptake of amyloid precursor protein (APP), which then fragmented into the neurotoxic amyloid-B42. “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,” explained Jinyu Fei, a graduate student and lead author of the study published in Science Advances.
The findings suggest preserving the MPS could offer a novel therapeutic strategy. “Preserving or stabilizing the MPS might offer a way to slow the early, hidden cellular changes that precede Alzheimer’s symptoms,” Fei added.
Super-Resolution Microscopy Reveals Active MPS Role
The prevailing understanding of the membrane-associated periodic skeleton (MPS) within neurons has long been as a static scaffold, primarily responsible for maintaining cellular shape. However, recent advances in super-resolution microscopy are challenging this view, revealing a dynamic and surprisingly active role for this lattice-like structure. Penn State researchers utilized this cutting-edge imaging technique – capable of resolving details 10,000 times smaller than a human hair – to observe neurons in culture, uncovering evidence that the MPS functions as a critical regulator of endocytosis, the process by which cells internalize external material.
The team didn’t simply observe the MPS; they actively manipulated it, disrupting or reinforcing its structure to assess its impact on cellular uptake. Disrupting the MPS led to a marked increase in the rate of endocytosis, demonstrating that the structure normally acts as a brake on this essential process. Accelerated uptake weakens the lattice, triggering molecular signals that further dismantle the structure, effectively opening more pathways for nutrient and protein entry. This suggests the MPS may act as a neuroprotective barrier, and preserving its integrity could offer a novel therapeutic avenue.
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.
Ruobo Zhou, assistant professor of chemistry, of biochemistry and molecular biology, and of biomedical engineering at Penn State
Disrupted MPS Accelerates Amyloid-B42 Uptake
Researchers at Penn State have uncovered a critical link between the membrane-associated periodic skeleton (MPS) and the uptake of amyloid-B42, a protein fragment heavily implicated in Alzheimer’s disease progression. The team’s experiments revealed a surprising dynamic: disrupting the MPS dramatically increased the rate of cellular uptake. This is particularly concerning when considering the context of Alzheimer’s, as the team modeled early disease stages by inducing neurons to produce extra amyloid precursor protein (APP). They found that weakening the MPS accelerated APP intake, subsequently leading to increased levels of amyloid-B42, a neurotoxic fragment.
MPS Breakdown Correlates with Neurodegenerative Disease
The Penn State team’s investigation extends beyond simply identifying the MPS as a structural component, revealing a critical link between its integrity and the onset of Alzheimer’s disease. Researchers designed experiments mirroring early Alzheimer’s stages, inducing neurons to overproduce amyloid precursor protein (APP), a key disease marker, and observed a direct correlation with MPS degradation. This suggests the MPS functions as a neuroprotective barrier, regulating the influx of potentially harmful substances. The team discovered a concerning feedback loop: increased endocytosis weakens the MPS lattice, triggering its own breakdown and further accelerating nutrient and protein uptake. This dynamic, while potentially beneficial for rapid neuronal responses, appears to contribute to a destructive cycle in neurodegenerative conditions.
