Neuron Lattice Structure May Guard Against Neurodegeneration

Brain cells are perpetually swallowing material from nan fluid that surrounds them - signaling molecules, nutrients, moreover pieces of their ain surfaces - in a process known arsenic endocytosis that is essential for learning, memory and basic neural upkeep. 

Now, new research by Penn State scientists has revealed this captious process whitethorn beryllium governed by a previously unknown molecular gatekeeper: a lattice‑like structure just beneath nan aboveground of brain cells, or neurons, called nan membrane‑associated periodic skeleton aliases MPS. 

In a study published coming (Feb. 11) successful nan journal Science Advances, the researchers demonstrated that nan MPS structure lining nervus cells acts arsenic a beingness gatekeeper for nearly every major shape of endocytosis. The structure, made of repeating rings of proteins, was antecedently known for helping neurons maintain their shape. The scientists said they now understand it plays a acold much progressive role by deciding wherever and erstwhile cells tin return things in. 

"For many, galore years we have been trying to understand this molecular mechanism, what benignant of machinery will thief to facilitate this process, because it's connected to neurodegenerative diseases," said Ruobo Zhou, adjunct professor of chemistry, of biochemistry and molecular biology, and of biomedical engineering, at Penn State and corresponding writer connected nan study. "When endocytosis - this nutrient uptake and regulation - goes wrong, past there's protein aggregation that will build up successful nan brain, which is nan hallmark of neurodegenerative diseases specified arsenic Alzheimer's and Parkinson's." 

As a postdoctoral researcher in 2013, Zhou was part of the Harvard squad 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 caller study, Zhou's squad was able to demonstrate that nan MPS is acold much active, behaving like a gatekeeper to serve as a benignant of cellular postulation control for all awesome forms of endocytosis. 

The squad utilized precocious super‑resolution microscopy, a type of imaging technique that tin adjacent into cells at the nanoscale - astir 10,000 times smaller than nan thickness of a quality hairsbreadth - to study neurons grown in petri dishes successful nan lab. They made circumstantial proteins grow inside nan neurons, truthful they could way them, and fed the neurons different molecules to study the uptake process erstwhile nan MPS was functioning successful its normal state. Then, they manipulated the MPS by breaking aliases protecting parts of nan building to see what nan encephalon compartment did successful response. 

When nan researchers disrupted nan MPS, neurons began taking in material acold much quickly, suggesting nan lattice usually acts arsenic a brake. But nan astir striking find was that the building will also break itself, nan researchers said. They found that accelerated endocytosis could weaken nan lattice and set off a affirmative feedback loop: Increased cellular uptake activated molecular signals that told proteins inside the brain cells to chop up parts of its skeleton, opening much doors and accelerating further nutrient and macromolecule uptake. 

"We discovered that this membrane skeleton is actively regulating the nutrient uptake process of neurons," Zhou said. "You tin think of it arsenic a gatekeeper, guarding this physical obstruction to not allow nutrient uptake to happen. When a neuron needs to take in a circumstantial nutrient, this gatekeeper will open nan gates and let it in." 

This move whitethorn thief neurons ramp up activity erstwhile accelerated responses are needed, Zhou explained, but it could besides person a downside. 

The researchers designed cellular experiments to mimic the early stages of Alzheimer's disease by making neurons nutrient other amyloid precursor macromolecule (APP), a cardinal marker of nan disease. They found that degrading nan MPS sped up the intake of APP. Once wrong neurons, APP clipped into amyloid‑B42, a neurotoxic part powerfully linked to Alzheimer's disease. With nan MPS weakened, neurons accumulated more and more of this harmful molecule and showed higher levels of markers for compartment death. 

"We created a exemplary which is very much like Alzheimer's disease and found that successful immoderate aging neurons, aliases neurons nether pathologic conditions, nan endocytosis of toxic proteins was enhanced, which caused stressing conditions, ultimately leading to neuron deaths," said Jinyu Fei, a postgraduate student successful nan chemistry department in Penn State's Eberly College of Science and lead writer connected nan study. 

The team's findings suggest that the MPS whitethorn service arsenic a neuroprotective barrier, slowing APP uptake and helping support toxic molecules successful check. Its breakdown, already observed in aging and neurodegenerative disease, could extremity neurons into a destructive rhythm of accrued amyloid accumulation and structural decay. Preserving this lattice, nan researchers suggested, could go a caller strategy for slowing neurodegeneration. 

"We think this could open nan doorway for future therapies such as a protein target for neurodegenerative illness treatment," Fei said. "Preserving aliases stabilizing nan MPS might connection a measurement to slow nan early, hidden cellular changes that precede Alzheimer's symptoms." 

Other authors connected nan insubstantial are Yuanmin Zheng, doctoral campaigner successful biomedical engineering; Caden LaLonde, fourth-year undergraduate student majoring in biochemistry and molecular biology; and Yuan Tao, postgraduate student at Penn State's Huck Institutes of Life Sciences. 

The National Institutes of Health funded this work.