A Simple Protein Offers New Hope Against Alzheimer’s Disease—Discovered Through a Tiny Worm!

Protein homeostasis designates cellular processes that regulate synthesis, folding, degradation and elimination of proteins in cells. It therefore plays a major role in the proper cellular functioning. But if this machinery is, defective proteins accumulate, which can lead to various diseases. Researchers recently discovered a cell protection mechanism hitherto unknown, based on a specific protein. It could open new paths for the treatment of neurodegenerative diseases.

Our cells make continuous proteins from their genes, in the endoplasmic reticulum. It all starts with the transcription of DNA by messenger RNA, in turn translated into a polypeptide chain. After some post-transduction changes, the chain folds up to become a functional protein. Only the properly folded proteins are exported from the endoplasmic reticulum. Finally, an intracellular mechanism eliminates proteins once their task is accomplished.

But with age, the capacity of cells to complete the entire process decreases. They start to synthesize defective proteins, while the “cleaning” system becomes unable to follow the cadence. Consequently, harmful proteins can agglutinate. However, this accumulation is toxic to cells because it increases cellular stress and disrupts physiological processes. This ends up leading to the inability of cells to maintain their function.

A protein that protects cell stress

“” If the cells undergo stress because the aggregation of proteins has started, the endoplasmic reticulum, where the proteins are manufactured and then released, receives the signal to stop the manufacture of these proteins. If it cannot correct the problem, the cell dies, which leads to the degeneration of neurons and neurodegenerative diseases that we observeS ”, explains Bhagwati Gupta, professor of biology at McMaster University.

Several studies have highlighted the protective role of a specific protein against increased cell stress. It is the neurotrophic factor derived from mesencephalic astrocytes (or manf, for Mesencepthalic astrocyte-derived neurotrophic factor). Its discovery dates back to the early 2000s. Canadian researchers had then shown its protective effect on dopaminergic neurons vis-à-vis the stress of the endoplasmic reticulum.

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It was also discovered that the Manf was essential for the survival of pancreatic beta cells. A more recent study has identified a intracellular receiver with which the Manf interacts directly to ensure neuronal survival in stress.

During previous works, Gupta and his team had themselves already shown that verses Caenorhabditis Elegans Genetically modified so as not to express the Manf had defects such as increased stress of the endoplasmic reticulum, a dopaminergic neurodegeneration and an abnormal aggregation of proteins.

All of these results suggested that the Manf play a crucial role in cellular processes. Given its therapeutic potential, it was essential to understand the mechanisms via which it regulates cellular functions. To do this, the researchers have studied in more detail its operation at C. Elegans.

A direct influence on the lifespan

Thanks to a system to manipulate the amount of manf in the worms, this time they highlighted the role of this protein in the elimination of abnormal proteins that accumulate in cells. C. Elegans has the advantage of being transparent, which allowed researchers to follow the cellular processes closely. “” We could literally see where the Manf was expressed in verses “Confirms Shane Taylor, who participated in research.

Fluorescence marking has thus indicated to researchers the specific tissue location of the protein. A further analysis has shown that it was inside cells in lysosomes.

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“” We could see him in all fabrics. The Manf was present in structures known as lysosomes, which are associated with the lifespan and the aggregation of proteins “, Specifies Gupta. Lysosomes are cell or cellular organelles containing various enzymes capable of digesting many types of molecules. They thus act as a system for the elimination of cellular waste, including toxic proteins.

During his experiences, the team observed that an over-expression of the Manf extended the life of the worms. In addition, it reduced protein aggregates and improved neuronal survival. These different actions are mediated by the transcription factor HLH-30/TFEB, a regulator of autophagy and lysosomal activity.

The Manf thus promotes proteostase, that is, all the mechanisms regulating the production, folding, transport and degradation of proteins in the cell, in order to maintain its homeostasis. It helps to break down protein aggregates to facilitate their expulsion and also serves to “activate” the intracellular cleaning system.

Better preventing human diseases related to age

“” Collectively, our results establish that Manf is an essential regulator of the response to stress, proteostase and aging “Concludes the team in Proceedings of the National Academy of Sciences. In other words, the Manf maintains healthy cells so that they can work better for longer.

The researchers highlighted a single action mechanism for Manf-1 in C. Elegans, which involves mediated signaling by HLH-30 to regulate autophagy and lysosomal function. Credits: Taylor et al., PNAS (2024)

Although this study involves only worms, researchers believe that their observations are based on universal processes, common to all animals, including man. They also plan to repeat their experiences on more complex animals.

Thus, these results offer new perspectives in the fighting of diseases related to aging. The activation of natural cellular cleaning systems by MANF could help prolong cell life and reduce damage related to aging.

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“” The discovery of the role of manf in celloshalar homeostasis suggests that it could be used to develop treatments for diseases that affect the brain and other parts of the body by targeting cellular processes, eliminating these toxic clusters in cells and keeping their health “Said Gupta.

Before potential therapy was born, it remains to identify the other actors with which the Manf interacts. Indeed, the general idea is not only to understand the processes involved, but also to try to improve them to make them more effective. “” We want to live longer and better health. This type of actor could help us “Concludes the professor.