Immature eggs have compartments in which they store and eliminate toxic substances called protein aggregates. If they are not destroyed, these toxins prevent the eggs from maturing properly and make the first phases of embryonic development unviable. The study, done in mice, reveals a possible cause of infertility in mammals, although it remains to be seen if the conclusions are valid in humans.
The results of the study, led by the Center for Genomic Regulation of Barcelona (CRG) and published this Tuesday in the journal Cell, help explain the almost unexplored mystery of the long life of eggs, which in species like humans remain healthy for almost 50 years.
“The egg is a super long-lived cell, it lives for decades, but it has to be kept clean, intact, to be able to pass all its components, in addition to the DNA, to the embryo,” Gabriele Zaffagnini explained at a press conference organized by Science Media Center Spain. , the CRG researcher who led the investigation.
Unlike the sperm, which only provides the embryo with genetic material, the eggs give it all the elements inside, so the challenge is twofold: they must live a long time and remain pristine inside. And all this without being able to divide, one of the main mechanisms that cells have to eliminate possible toxic substances that threaten their proper functioning.
The success could be explained by the absence of toxic substances inside the cell, but CRG researchers have shown that this is not the case. “We have found that eggs have protein aggregates”, sets of defective proteins that accumulate, are toxic and can end up killing cells. In neurons, which do not divide either, for example, the presence of these aggregates is related to neurodegenerative diseases such as Alzheimer's, Parkinson's or ALS.
On the other hand, in oocytes – immature eggs – these aggregates exist but do not interfere with the health of the cell. Scientists have discovered that this occurs because they are not distributed throughout the cell interior, but are concentrated within very large compartments that they have called ELVAs.
“An ELVA is an agglomerate of vesicles that sequesters the aggregates and keeps them in a non-toxic state, not harmful to the cell,” describes Zaffagnini. “This is very novel, it was very unexpected at first, because normally all the vesicles that make up the ELVAs are found as individual vesicles, while here they are all stuck together in a single agglomerate.”
The vesicles that the expert talks about are a group of particles responsible for degrading toxic substances, and are other tools that cells have to stay healthy. They usually work independently, each one on its own, but in the case of oocytes they are joined by a protein that acts as glue, and which gives the ELVAs special properties.
An ELVA “behaves as something more than the sum of its components,” describes the author. Unlike individual vesicles, agglomerates act like a fluid, and can stick together like oil droplets in water; they move through the interior of the cell capturing protein aggregates and keeping them harmless; and, more importantly, they have an autonomous function.
Typically, vesicles present inside cells degrade protein aggregates immediately. ELVA, on the other hand, store them inside and do not degrade them until the egg matures. “We believe that this is a kind of form of energy saving,” says the leader of the research. “The egg has to survive for a long time, and keeping these structures constantly active would be a great energetic cost.”
Now, when the egg matures, it is essential that it eliminates toxic substances before being fertilized. The team has observed that if the aggregates remain inside the cell once the sperm has fertilized the egg, it does not reach the first phases of embryonic development. Therefore, they conclude, the absence or poor functioning of these compartments is a possible cause of infertility.
Now, they are immersed in checking whether these mechanisms that guarantee the long-term viability of the eggs are altered in elderly mice and, therefore, with fertility problems. Preliminary results show that ELVAs act defectively, says Zaffagnini, “now we have to understand why and what the consequences are.”
At the same time, the team is collaborating with fertility clinics to analyze human eggs, and see if both the problem and the solution in our species coincide with what has been observed in mice. That is, if the presence of protein aggregates defines the poor quality of the eggs, and if we have ELVAs that store and eliminate them in due time.
Another unknown that remains to be resolved is whether, once again, there is some parallel between what happens in the eggs and what happens in the neurons. Beyond the fact that the aggregation of defective proteins is associated with neurodegeneration, do these cells have a method, when they are healthy, to eliminate toxins?
The protein that keeps the egg vesicles stuck together and gives structure to the ELVAs belongs to the same family as the one that is responsible for their distribution inside neurons. “It is possible that on a smaller scale there are things similar to ELVAs that have not yet been detected,” concludes Zaffagnini, who sees another avenue for future research here.
