Age-Related Diseases: What if Misfolded Proteins Were Involved?

Science

Our knowledge of the chemistry of aging and age-related diseases continues to improve. New research suggests that these diseases are caused by protein-folding abnormalities, whereby proteins are exposed to oxidation and their functioning is modified.

Why is aging – which is not a disease in itself – linked to so many conditions, such as cardiovascular, neurodegenerative and autoimmune diseases, not to mention cancer? There have to be underlying biological mechanisms at play which mean that the risk of developing such diseases increases with age.

The finger is often pointed at reactive oxygen species (ROS), which result from energy metabolism reactions. These oxidize cell components and gradually damage cells. But for Miroslav Radman*, winner of the 2003 Inserm Grand Prize, their responsibility for the onset of age-related diseases depends on the resistance of proteins to oxidation.

The majority of proteins are in fact folded back on themselves in such a way as to be protected from this phenomenon. However, the slightest defect in their structure can make them vulnerable to oxidation. According to an analysis of the scientific literature that was followed by a series of experiments, Radman considers that such defects are the result of genetic polymorphism: they vary from one person to another, which would explain the differences in individual susceptibility to aging.

"Genetic polymorphism – it is because of these genetic variations that we all have different DNA. It is estimated that for 20,000 protein species, there are 30,000 amino acids that differ from one individual to the next [amino acids being the building blocks that form the proteins], explains Radman. Most of these differences are silent mutations that do not cause disease at birth. But as the decades pass, they are not always without consequences". Indeed, some are linked to a variability in protein folding time following its production. And if this time is prolonged, some amino acids risk becoming oxidized before the protein has adopted the definitive form that will protect it. This early oxidation prevents the protein from folding, "it paralyses it", says Radman. This can then modify its activity and lead to functional defects.

Protein oxidability linked to earliness of age-related disease onset

Radman has confirmed these hypotheses in vitro. With Anita Krisko, from the Mediterranean Institute for Life Sciences (MedILS) in Split, Croatia, he studied this phenomenon in connection with Parkinson’s disease. This pathology is linked to alpha-synuclein protein abnormalities. The researchers studied the impact of the polymorphism of this protein on its malformation rate. "Two variations associated with Parkinson’s disease were described: one at amino acid 53 and the other at position 30. They are respectively linked to its onset at around age 30 and age 50-60, on average". By purifying the proteins derived from genes carrying these variations and then by exposing them to potent oxidant agents, Radman and Krisko saw that the protein derived from variation 53 was more poorly formed and oxidized than that carrying variation 30. Consequently, at least in this example, protein oxidability is linked to earliness of disease onset.

The good news is that the level of protein oxidation is reversible thanks to protein renewal, among other things. This opens up the possibility of preventing and even curing certain diseases. "Administering molecules able to bind to misfolded proteins can protect them from oxidation", clarifies Radman. He tested this approach on skin cells taken from elderly subjects in which he obtained reduced oxidation of their proteins and rejuvenation of the cells. They regained a more youthful morphology, the improved ability to divide in culture and they presented a reduction in markers of aging (SA-βgal, p16ink4). Ultimately, the researcher hopes to use them in a preventive and therapeutic strategy against age-related diseases.

Note:
* unit 1016 Inserm/CNRS/Université Paris Descartes, Institut Cochin, Emeritus Professor at Université Paris-Descartes and founder of the Mediterranean Institute for Life Sciences (MedILS, Split, Croatia)

Source : Krisko A, Radman M. Protein damage, ageing and age-related diseases. Open Biol; 9(3):180249. https://doi.org/10.1098/rsob.180249