1706102554 The Frontiers of Knowledge Award recognizes researchers who have

The Frontiers of Knowledge Award recognizes researchers who have explained how proteins work and the role they play in disease

The Frontiers of Knowledge Award recognizes researchers who have

The BBVA Foundation's Frontiers of Knowledge Prize in Biology and Biomedicine, endowed with 400,000 euros, was awarded to the German Ulrich Hartl from the Max Planck Institute for Biochemistry, the American Arthur Horwich from Yale University and the Japanese Kazutoshi Mori from Kyoto University and the German Peter Walter of the University of California at San Francisco and Altos Labs for their discoveries about the cellular machinery on which protein folding depends. The findings are useful for understanding the origins of many diseases, from Alzheimer's to cancer, and developing therapies to treat them.

The DNA in our cells contains all the instructions we need for development, survival and reproduction. However, proteins are primarily responsible for carrying out these functions, and “in order to fulfill their function,” as the jury report states, “they must adopt certain three-dimensional structures, which are achieved in cells with the help of a group of proteins accompanying persons. “. The four winners made two important discoveries in this field: Hartl and Horwich discovered the first cellular pathway that regulates protein folding, thanks to the discovery of the role of the so-called chaperone Hsp60, while Mori and Walter identified the mechanism used by cells when protein folding fails acted on them either to try to fold them properly or, if this is not possible, to destroy them.

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These insights into a biological process so crucial to life have enormous biomedical implications, as the molecular machinery that controls both protein folding and the response to errors in this mechanism is implicated in the development of numerous diseases, from cancer to neurodegenerative Diseases such as Alzheimer's. Parkinson's and amyotrophic lateral sclerosis (ALS) or the aging process itself. For all these reasons, the jury concluded in its minutes that the “revolutionary findings” of the four winners showed “how cells control the biogenesis and degradation of proteins, which “It is fundamental not only to physiology but also to understanding the origin and design of therapies for many diseases.”

“The results of the four winners are important not only for our understanding of basic biology, but also because they lead to a new way of understanding diseases and their better treatment in the future,” emphasizes Dario Alessi, director of the unit. of Protein Phosphorylation and Ubiquitination at the MRC, University of Dundee (UK) and member of the jury. “Especially in the field of neurodegeneration, there is currently enormous interest in promoting therapeutic pathways that can maintain correctly folded proteins in cells, and also in promoting the process of eliminating unfolded proteins, since this is harmful to the cells. In addition, it is thought that in the case of cancer, the ability to eliminate cancer cells, which grow very quickly and are highly dependent on this process, could be increased by inhibiting the enzymes that cause protein folding in some types of tumors could. .

In 1972, Christian Anfinsen received the Nobel Prize for a series of experiments that showed that certain small proteins fold spontaneously in a test tube. Hartl and Horwich questioned the spontaneous function of proteins while working with mutant yeast. The researchers found that the proteins did not fold properly in the absence of the Hsp60 protein, which was missing in the mutant microorganisms. Today's winners concluded that this molecule acted as a chaperone and was necessary for protein folding. In a paper 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 the response to misfolded proteins (unfolded protein response or UPR), a process that strengthens the therapeutic possibilities of this knowledge.

“The cell is a ruthless world, a place where there are large concentrations of proteins constantly beating each other. “Chaperones provide a suitable environment for proteins in another way so that they can fold in the hostile environment of the cell without unwanted interactions,” explains José María Valpuesta, director of the Department of Macromolecular Structures at the National Center for Biotechnology in Madrid.

When a cell's ability to fold proteins is exceeded by the amount of proteins being folded, or when folding conditions are under stressful conditions (e.g. due to lack of oxygen or nutrients), proteins will not fold properly and become toxic due to aggregation phenomena and must be repaired or eliminated through a process that plays a comparable role to a “trash can that needs to be emptied,” adds Dario Alessi. Additionally, while this machinery is running, cellular processes that produce more proteins are “paused” until the cell “reboots” and returns to normal functioning.

The four winners believe that their insights into the molecular machinery that regulates both protein folding and errors in this process can advance the development of new effective treatments against multiple diseases and even contribute to understanding and managing the aging process. “What Parkinson's, Alzheimer's, Huntington's and possibly ALS have in common is that after a certain age, patients develop problems in their brain and nerve cells due to the accumulation of misfolded proteins. In general, the probability of this is significantly higher as you get older,” explains Hartl. For this reason, the Max Planck Institute researcher believes that these disorders could be combated by “intervening in the production of proteins that accumulate.” In fact, he points out that important experimental progress has already been made in applying this therapeutic strategy against ALS and Huntington's disease.

According to Óscar Millet, principal investigator at the Laboratory of Precision Medicine and Metabolism at the CIC bioGUNE in Bilbao, there are currently “a whole range of pharmacological interventions that try to mimic the action of chaperones with the so-called drug chaperone.” molecular chaperones, which would be chemical molecules, which simply combine with the protein and act as a chaperone.”

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