The BBVA Foundation Frontiers of Knowledge Prize in Biology and Biomedicine, worth 400,000 euros, has been awarded to the German Ulrich Hartl, from the Max Planck Institute of Biochemistry, the American Arthur Horwich, from Yale University, the Japanese Kazutoshi Mori, from the Kyoto University, and the German Peter Walter, from the University of California in San Francisco and Altos Labs, for their discoveries about the cellular machinery on which protein folding depends.
The finding is useful for understanding the origin of many diseases, from Alzheimer's to cancer, and developing therapies to treat them.
The DNA of our cells contains all the instructions we need to develop, survive and reproduce.
But the main ones responsible for carrying out these functions are proteins and "to fulfill their function", as explained in the jury report, "they must adopt certain three-dimensional structures that are achieved in cells with the help of a group of proteins called chaperones. ”.
The four winners made two key discoveries in this field: Hartl and Horwich discovered the first cellular pathway that regulates protein folding, thanks to the discovery of the role played by the so-called chaperone Hsp60, while Mori and Walter identified the mechanism used by cells when protein folding fails, acting on them, either to try to fold them correctly or, if this is not possible, destroy them.
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These findings about a biological process so crucial for life have enormous biomedical implications, since the molecular machinery that controls both protein folding and the response to failures in this mechanism is involved in the origin of multiple diseases, from cancer to neurodegenerative disorders such as Alzheimer's, Parkinson's and amyotrophic lateral sclerosis (ALS), or the aging process itself.
For all these reasons, the jury concludes its minutes by highlighting that the “revolutionary findings” of the four winners have revealed “how cells control the biogenesis and degradation of proteins, something fundamental not only for physiology, but also for understanding the origin and design therapies for many diseases.”
“The findings of the four winners are important not only for our understanding of fundamental biology, but also because they lead to a new way of understanding diseases and treating them better in the future,” highlights Dario Alessi, director of the Unit. of Protein Phosphorylation and Ubiquitination at the MRC at the University of Dundee (United Kingdom) and member of the jury.
"There is currently enormous interest, especially in the field of neurodegeneration, to promote therapeutic avenues that can maintain correctly folded proteins in cells, and also to promote the process of elimination of unfolded proteins, because this is detrimental to the cells.
Furthermore, in the case of cancer, it is thought that if the enzymes that cause protein folding in some types of tumors could be inhibited, this could increase the ability to eliminate cancer cells that grow very quickly and are highly dependent on this process. ”.
In 1972, Christian Anfinsen received the Nobel Prize for a series of experiments showing that certain small proteins fold spontaneously in a test tube.
Working with mutant yeast, Hartl and Horwich questioned the spontaneous functioning of proteins.
The researchers saw that in the absence of the Hsp60 protein, which was absent in the mutant microorganisms, the proteins did not fold correctly.
This molecule, today's winners deduced, acted as a chaperone and was necessary for protein folding.
In an article published in Nature in 1989 they presented their discovery and overthrew Anfinsen's dogma.
Later, Mori and Walter simultaneously, but independently, discovered the mechanism of response to misfolded proteins (in English,
unfolded protein response
or UPR), a process that reinforces the therapeutic possibilities of this knowledge.
“The cell is a ruthless world, a place where there are large concentrations of proteins, continually beating each other.
Chaperones provide proteins, in a different way, with a suitable environment so that they can fold without unwanted interactions, in the hostile environment of the cell," explains José María Valpuesta, director of the Department of Macromolecular Structures at the National Center of Biotechnology in Madrid.
When a cell's ability to fold proteins is exceeded by the amount of proteins to be folded, or when folding conditions are under stress conditions (for example, due to lack of oxygen or nutrients), Proteins fail to fold correctly, becoming toxic due to aggregation phenomena and must be repaired or eliminated by a process that plays a role comparable to that of a “garbage can that must be emptied,” adds Dario Alessi.
Furthermore, while this machinery is running, cellular processes that make more proteins are “paused” until the cell “reboots” and functions normally again.
The four winners are convinced that their findings on the molecular machinery that regulates both protein folding and failures in this process can drive the development of new effective treatments against multiple diseases and even contribute to understanding and acting on the aging process. .
“Parkinson's, Alzheimer's, Huntington's disease and possibly ALS have in common that, at a certain age, patients develop problems in their brain, with their nerve cells, due to the accumulation of misfolded proteins.
In general, the likelihood of this happening is much higher as you get older,” explains Hartl.
For this reason, the Max Planck Institute researcher believes that these disorders could be combated by “interfering with the production of proteins that accumulate.”
In fact, he points out that important experimental advances have already been achieved in the application of this therapeutic strategy against ALS and Huntington's disease.
According to Óscar Millet, principal researcher at the Laboratory of Precision Medicine and Metabolism at CIC bioGUNE in Bilbao, there is currently “an entire line of pharmacological intervention that is trying to emulate the effect of chaperones with what is called the drug chaperone. , or molecular chaperones, which would be chemical molecules that simply associate with the protein and act as a chaperone.”
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