Brain cells\u00a0are constantly swallowing\u00a0material\u00a0from the fluid that surrounds\u00a0them\u00a0–\u00a0signaling molecules, nutrients, even pieces of their own surfaces\u00a0–\u00a0in a process known as endocytosis\u00a0that\u00a0is\u00a0essential for learning,\u00a0memory\u00a0and basic\u00a0neural\u00a0upkeep.\u00a0<\/p>\n
Now,\u00a0new\u00a0research\u00a0by Penn State scientists\u00a0has\u00a0revealed\u00a0this vital process may be governed by\u00a0a\u00a0previously unknown\u00a0molecular\u00a0gatekeeper:\u00a0a\u00a0lattice\u2011like structure\u00a0just beneath the surface of\u00a0brain cells, or\u00a0neurons,\u00a0called the membrane\u2011associated periodic skeleton or MPS.\u00a0<\/p>\n
In a study published today (Feb. 11) in the journal\u00a0Science Advances,\u00a0the\u00a0researchers\u00a0demonstrated\u00a0that the MPS\u00a0structure lining nerve cells\u00a0acts as a physical gatekeeper for\u00a0nearly every\u00a0major form of endocytosis. The structure, made of repeating rings\u00a0of\u00a0proteins, was previously known for helping neurons\u00a0maintain\u00a0their shape.\u00a0The scientists said they now understand\u00a0it plays a far more active role\u00a0by\u00a0deciding where and when cells can take things in.\u00a0<\/p>\n
“For many, many years\u00a0we\u00a0have been trying to\u00a0understand this\u00a0molecular mechanism, what kind of machinery will help to facilitate this process,\u00a0because it’s\u00a0connected to\u00a0neurodegenerative diseases,” said\u00a0Ruobo\u00a0Zhou, assistant professor of chemistry,\u00a0of\u00a0biochemistry and molecular biology, and of biomedical engineering,\u00a0at Penn State and corresponding author on the study. “When\u00a0endocytosis\u00a0–\u00a0this nutrient uptake and regulation\u00a0–\u00a0goes wrong, then there’s protein\u00a0aggregation that\u00a0will build up in the brain, which is the hallmark of\u00a0neurodegenerative diseases such as Alzheimer’s and Parkinson’s.”\u00a0<\/p>\n
As a postdoctoral researcher\u00a0in 2013, Zhou was\u00a0part of\u00a0the Harvard team that first discovered the\u00a0skeleton\u00a0structure\u00a0inside neurons\u00a0that researchers thought was\u00a0a passive support structure.\u00a0Using\u00a0super-resolution imaging\u00a0of cultured neurons\u00a0in this new study, Zhou’s team was able\u00a0to\u00a0demonstrate\u00a0that the MPS\u00a0is far more active,\u00a0behaving\u00a0like a gatekeeper\u00a0to serve\u00a0as a kind of\u00a0cellular traffic control\u00a0for\u00a0all major forms of endocytosis.\u00a0<\/p>\n
The team used advanced super\u2011resolution microscopy, a type of imaging\u00a0technique\u00a0that can peer into cells at\u00a0the\u00a0nanoscale\u00a0– about 10,000 times smaller than the thickness of a human hair –\u00a0to study neurons\u00a0grown\u00a0in petri dishes in the lab. They made specific proteins\u00a0grow\u00a0inside the neurons, so they could track them, and fed\u00a0the\u00a0neurons\u00a0different molecules to\u00a0study\u00a0the uptake process when the MPS was functioning in its normal state. Then, they\u00a0manipulated\u00a0the MPS by\u00a0breaking or protecting parts of the structure to\u00a0see what the brain cell did in response.\u00a0<\/p>\n
When the researchers disrupted the MPS, neurons began\u00a0taking in\u00a0material far more quickly, suggesting the lattice normally acts as a brake. But the most striking discovery was that\u00a0the structure will\u00a0also\u00a0break itself, the researchers said.\u00a0They\u00a0found that accelerated endocytosis could weaken the lattice and\u00a0set\u00a0off a positive feedback loop: Increased cellular uptake\u00a0activated\u00a0molecular signals that told\u00a0proteins\u00a0inside\u00a0the\u00a0brain cells\u00a0to chop up parts of\u00a0its\u00a0skeleton, opening more doors and accelerating further nutrient and protein uptake.\u00a0<\/p>\n
“We discovered that this\u00a0membrane skeleton\u00a0is actively regulating\u00a0the nutrient uptake process of neurons,” Zhou\u00a0said.\u00a0“You can think\u00a0of it as a gatekeeper,\u00a0guarding this\u00a0physical barrier to not allow\u00a0nutrient uptake to happen.\u00a0When\u00a0a\u00a0neuron needs to take\u00a0in\u00a0a specific nutrient, this\u00a0gatekeeper will\u00a0open the gates and\u00a0let it in.”\u00a0<\/p>\n
This dynamic may help neurons ramp up activity when rapid responses are needed, Zhou explained, but it could also have a downside.\u00a0<\/p>\n
The researchers designed\u00a0cellular\u00a0experiments\u00a0to\u00a0mimic\u00a0the\u00a0early stages\u00a0of Alzheimer’s disease\u00a0by\u00a0making\u00a0neurons produce extra amyloid precursor protein (APP),\u00a0a key marker of the disease. They\u00a0found that degrading the MPS sped up the\u00a0intake\u00a0of\u00a0APP.\u00a0Once inside neurons, APP clipped into amyloid\u2011B42, a neurotoxic fragment strongly linked to Alzheimer’s\u00a0disease. With the MPS weakened, neurons accumulated\u00a0more\u00a0and more\u00a0of this harmful\u00a0molecule\u00a0and showed higher levels of markers for cell death.\u00a0<\/p>\n
“We created a model which is very\u00a0much\u00a0like Alzheimer’s disease\u00a0and found\u00a0that in some aging neurons, or neurons under pathologic conditions, the endocytosis of toxic proteins was\u00a0enhanced, which\u00a0caused\u00a0stressing conditions,\u00a0ultimately\u00a0leading to neuron deaths,” said Jinyu Fei, a graduate student in the chemistry department\u00a0in\u00a0Penn State’s Eberly College of Science and lead author on the study.\u00a0<\/p>\n
The\u00a0team’s\u00a0findings suggest\u00a0that\u00a0the MPS may serve as a neuroprotective barrier, slowing APP\u00a0uptake\u00a0and helping keep toxic molecules in check. Its breakdown,\u00a0already\u00a0observed\u00a0in aging and neurodegenerative disease,\u00a0could tip neurons into a destructive cycle of increased amyloid production and structural decay.\u00a0Preserving this lattice, the researchers suggested, could become a new strategy for slowing neurodegeneration.\u00a0<\/p>\n
“We think\u00a0this could\u00a0open the door for future\u00a0therapies\u00a0such as\u00a0a\u00a0protein target for neurodegenerative disease treatment,” Fei said.\u00a0“Preserving or stabilizing the MPS\u00a0might offer a way to slow the early, hidden cellular changes that precede Alzheimer’s symptoms.”\u00a0<\/p>\n
Other authors on the paper are\u00a0Yuanmin\u00a0Zheng, doctoral candidate in biomedical engineering;\u00a0Caden LaLonde, fourth-year undergraduate student\u00a0majoring in\u00a0biochemistry and\u00a0molecular\u00a0biology;\u00a0and Yuan Tao, graduate student\u00a0at\u00a0Penn State’s\u00a0Huck Institutes of Life Sciences.\u00a0<\/p>\n
The National Institutes of Health funded this work.\u00a0<\/p>\n
Source:<\/p>\n
Journal reference:<\/p>\n