A driving force behind cellular ‘protein factories’

Researchers have identified the driving force behind a cellular process linked to neurodegenerative disorders such as Parkinson’s Disease and motor neurone disease.

In a study published today in Advances in science, researchers from the University of Cambridge show that the biological engines behind efficient protein production are tiny parts within the cell.

The endoplasmic retopulum (ER) is the cell’s protein factory, producing and modifying the proteins needed to ensure healthy cell function. This is the largest organelle in the cell and is in a structure resembling a web of tubes and leaves. The ER moves rapidly and constantly changes shape, expanding across the cell to where it is needed at any given moment.

Using high-resolution microscopy methods, researchers from Cambridge’s Department of Chemical Engineering and Biotechnology (CEB) have discovered the driving force behind these movements – a fracture that could have a major impact on research. neurodegenerative diseases.

“The endoplasmic reticulum is known to have a highly vascular structure – constantly stretching and expanding its shape inside the cell,” said Dr. Meng Lu, a research researcher in the Laser group Analytics, led by Professor Clemens Kaminski.

“The ER needs to be able to reach all locations efficiently and quickly to perform essential housekeeping tasks within the cell, wherever and wherever it is needed. Damage this potential linked to diseases including Parkinson’s, Alzheimer’s, Huntington’s Disease and ALS has so far been little understood in how the ER achieves these rapid and interesting changes in shape and how it responds to cell stimuli. ”

Lu and his colleagues discovered that another cell component holds the keys – tiny structures, resembling tiny droplets in organs, called lysosomes.

Lysosomes can be thought of as the recycling centers of cells: they capture damaged proteins, breaking them down in their original building blocks until they are reused in the production of new proteins. Lysosomes also act as sensory centers – building up environmental nuclei and communicating them with other parts of the cell, which adapt accordingly.

Up to 1,000 or so lysosomes can move around the cell at one time and with them, the ER appears to change its shape and position, in a similar orchestrated manner.

What surprised Cambridge scientists was that they found a causal link between the movement of the tiny lysosomes in the cell and the remodeling process of the large ER network.

“We could show that it is the movement of the lysosomes themselves that causes the ER to remodel in response to cell stimuli,” Lu said. “When the cell senses the need for lysosomes and ERs to travel to distal corners of the cell, the lysosomes pull the ER net with them, like tiny locomotives.”

From a biological point of view, this makes sense: The lysosomes act as a sensor inside the cell, and the ER as a unit of response; coordination of synchronous action is essential for cell health.

To discover this amazing connection between two very different organelles, Kaminski’s research team made use of new imaging technologies and machine learning algorithms, which gave them unprecedented insights into the inner workings of the cell.

“It is interesting that we are now able to look inside living cells and see the amazing speed and dynamics of cellular devices in such detail and in real time,” Kaminski said. “Just a few years ago, it would have been unbelievable to watch organelles go about their business inside the cell.”

The researchers used illumination patterns predicted on living cells at high speed, and an advanced computer algorithm to obtain information at a scale more than one hundred times smaller than the width of human hair. It has recently been possible to capture such information at video levels.

The researchers also used machine learning algorithms to simulate the structure and movement of ER networks and lysosomes in an automated fashion from thousands of data sources.

The team expanded their research to look for neurons or zero cells – specific cells with long protrusions called axons on which signals are transmitted. Axons are very thin tubular structures and it was not known how the movement of the very large ER network is directed within these structures.

The study shows how lysosomes travel easily on the axons and drag the ER behind them. The researchers also show how badly this process adversely affects the development of growing neurons.

Researchers often observed incidents where the lysosomes acted as repair engines for fragmented or broken ER pieces, reuniting them and re-connecting them into a complete network. So the work is relevant for understanding and repairing disorders of the nervous system.

The team also studied the biological significance of this twin movement, stimulating – in this case nutrition – the sensory lysosomes. The lysosomes were seen moving towards this signal, dragging the ER network backwards so that the cell received an appropriate response.

“Until now, little was known about the management of ER structure in response to metabolic signals,” Lu said. “Our research provides a link between lysosomes as sensory units that actively direct local ER response.”

The team hopes that their ideas will be of great use to those exploring the links between disease and cell response, and their next steps are aimed at studying ER function and disorder. the diseases such as Parkinson’s Disease and Alzheimer’s.

Neurodegenerative disorders are associated with the accumulation of damaged and misfolded proteins, so understanding the basic mechanisms in ER action is essential for studying their treatment and prevention.

“The discoveries of the ER and lysosomes won the Nobel Prize many years ago – they are key organelles essential for healthy cell function,” Kaminski said. “It’s interesting to think that there is still so much to learn about this system, which is crucial for basic biochemical science that is trying to find the cause and cure of these devastating diseases.”


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