Dementia and its impact on neurons: Why do some survive and others don't?

A study analyzed the cellular mechanisms linked to neurodegenerative disorders and evaluated the reasons why certain nerve structures maintain their integrity. The details

                                                                                         

 

A research team from University College London (UCL) has identified clues as to why some nerve cells die in dementia and others do not.

The study, published in Cell Reports, used fruit fly models to analyze cellular differences in the development of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The work is part of a line of research that seeks to understand what biological mechanisms allow certain neurons to resist pathological processes.

It should be noted that FTD is a group of brain diseases that manifest primarily in the frontal and temporal lobes, regions linked to language, behavior, and personality. ALS is a nervous system disorder that damages neurons in both the brain and spinal cord.

                                                                                        

The research examined why some nerve cells in the brain of Drosophila melanogaster are resistant to processes related to FTD and ALS in humans. Other neurons, however, showed greater vulnerability.

Lead author Teresa Niccoli, from the UCL Institute of Healthy Ageing and the UCL Biosciences Department, said: “In dementia, we find that some parts of the brain are affected and others are not. For example, in frontotemporal dementia (FTD), the first to be affected are the neurons in the front of the brain (the part responsible for processing language, emotions, and behavior).”

Meanwhile, in a UCL statement, the authors asked: “Why are some nerve cells affected and others not? This is one of the most important unknowns in dementia research.”

Thus, for Niccoli, "if we understand what makes some nerve cells resistant to diseases that cause dementia, we could discover new treatments to stop these diseases."

                                                                                      

Niccoli is studying a population of fruit flies with a mutation in the C9orf72 gene, the most common cause of both FTD and ALS in humans, the authors reported.

“People with changes in this gene tend to have a buildup of harmful protein clumps in their nerve cells, eventually leading to FTD or ALS. In a previous study, Niccoli identified that changes in the C9orf72 gene caused the flies' brains to process sugar differently,” they wrote in the statement.

Now, the expert and author “is using cutting-edge technology to explore why some fly nerve cells are more resilient to damage,” they detailed.

The study identified a particular trait in the cells that resist the effects of the C9orf72 mutation. Neurons were more likely to survive if they were more efficient at removing harmful protein debris.

                                                                                

“Let's think of the fly brain as a city. The brain is a city made up of different 'neighborhoods,' some of which dispose of their waste better than others. Neighborhoods with good waste management measures, such as regular garbage collection and efficient recycling systems, adapt better to an unexpected event (like a flood or a chemical spill) than neighborhoods that don't have these systems,” Niccoli said.

He added: “When we looked at nerve cells from flies with genetic changes linked to FTD and ALS, those that were better equipped to remove protein waste survived, while those that didn't died. We then took a closer look at why these cells were able to survive despite the accumulation of harmful proteins.”

For that analysis, Niccoli applied a technique called single-cell RNA sequencing, which allows the behavior of individual nerve cells to be studied. With this technology, he was able to detect subtle differences between the resilient cells and those that failed to survive.

                                                                                    

In resilient neurons, they identified an increase in the activity of a protein involved in waste removal, called Xbp1. By artificially increasing the presence of Xbp1 in flies, the researchers observed an improvement in the brain's ability to handle the toxic effect of the protein buildup caused by the mutation.

This finding suggests that in fruit flies, boosting Xbp1 activity could offer a form of protection against the effects of C9orf72. However, it has not been established whether this effect can be replicated in human neurons.

Creating a detailed map of individual neuronal activity is feasible in animal models such as flies, due to their small brain size. It is unclear whether the same principles observed in these insects apply to more complex organisms. Future research will seek to elucidate this possibility.

Niccoli anticipated the team's next steps: "Our next steps will be to analyze whether boosting proteins involved in protein clearance increases resilience to changes in C9orf72 in human nerve cells cultured in the lab and in mouse studies. This will give us a better understanding of whether targeting Xbp1 or similar proteins in humans could help us discover new drugs for FTD or ALS."