Cellular waste disposal, occurring through an interaction of autophagy and lysosomes, keeps cells young and protects, for example, against protein aggregation which occurs in neurodegenerative diseases. Researchers from the Leibniz Research Institute for Molecular Pharmacology (German acronym: FMP) in Berlin have shown for the first time that water loss in the cell, the so-called osmotic stress, sets this important system in motion.
Our cells need a "spring-cleaning" from time to time so that misfolded protein molecules or damaged cell organelles are broken down and the protein molecules do not clump together. Responsible for this degradation is the so-called autophagy and the closely linked lysosomal system, the discovery of which was honored with the Nobel Prize for Medicine in 2016.
Several studies suggest that autophagy and lysosomes play a central role in cell aging and neurodegenerative diseases. Moreover, it seems certain that fasting or food deprivation can initiate this cellular degradation and recycling process. Otherwise little is known about how cells and organs control the quality of their protein molecules and which environmental influences give the decisive signal to activate the “clean up”.
Scientists from the FMP in Berlin have now identified a new trigger: Osmotic stress, i.e. the state in which cells lose water, boosts the system of autophagy and lysosomal degradation.
"When there is dehydration, we suddenly see more lysosomes in the cells, i.e. more of the organelles in which the degradation of aggregated protein molecules takes place," explained study co-author Dr. Tanja Maritzen, adding that "this is a clever adaptation since the cellular loss of water simultaneously promotes the aggregation of proteins. These agglutinations have to be broken down quickly in order to keep the cells functional, and this works better if the cells have more lysosomes".
The researchers were able to observe what happens at the molecular level in the dehydrated cells using astrocytes, star-shaped brain cells that support our nerve cells in their work: When water is withdrawn, the ion transporter NHE7 migrates from the cell interior, where it is normally located, to the plasma membrane. This causes sodium ions to enter the cell, which indirectly increases the concentration of the important messenger calcium in the cytosol. The increased calcium concentration in turn activates a protein known as TFEB, a transcription factor that eventually switches on autophagy and lysosomal genes. The system is thus initially booted by the ion transporter NHE7 - triggered by osmotic stress.
"We did not know this way at all," said Prof. Dr. Volker Haucke, head of the research group and secondary author of the study: "This is a completely new mechanism for us, which responds to a completely different kind of physiological challenge than it was previously known”.
Counter-experiments showed how important this path is for human health: If the researchers removed a component of the signaling pathway, for example, the transporter NHE7 or the TFEB, then aggregated protein molecules accumulated in the astrocytes under osmotic stress conditions; that is, they could not be degraded. This was shown for synuclein, a protein involved in Parkinson's disease, among other things.
"Neurodegenerative diseases, in particular, are a possible consequence if this pathway is not switched on correctly," said Tania López-Hernández, a post-doctoral fellow in Prof. Hauckes and Dr. Maritzen's research groups and first author of the paper: "In addition, NHE7 is a so-called Alzheimer's risk gene. Now we have new insights as to why this gene could be so critical."
It is also interesting to note that a mental disability inherited on the X chromosome in boys is due to a mutation in the NHE7 gene. The researchers suspect that the disease mechanism is related to the degradation mechanism now described. If only the switch, i.e. the NHE7 protein, were defective, an attempt could be made to switch on the pathway in a different way.
"Repairing a genetic defect is practically very difficult and extremely expensive, but one could imagine pharmacologically influencing the NHE7 protein or using other stimuli such as the food supplement spermidine to switch on the autophagy system in these patients," said Volker Haucke, a cell biologist and researcher at the NeuroCure Cluster of Excellence in the Neurosciences, Charité Medical University in Berlin.
However, in order to be able to carry out such interventions, some basic questions need to be further researched. For example, it is still unclear how osmotic stress causes the migration of NHE7 to the cell surface. It is also not known whether the entire degradation system is activated or only individual genes are switched on, or what specific responses to osmotic stress are required to activate the lysosomal system. It is also unclear with which further stimuli this physiological process can be initiated.
The researchers now want to answer all these questions in follow-up projects. "We have learned from our work how fundamentally our water and ion balance affects the ability of our cells and tissues to break down defective protein molecules," concluded Haucke. "Now we want to understand this mechanism even better - also because it is of great importance for aging, neurodegeneration, and the prevention of a number of diseases.