Protein misfolding is strongly associated with age-related degenerative diseases
Aging and stress, stress and aging—these two human conditions, when paired, can profoundly affect the quality of life. When events go awry, molecular processes take place that, over time, can lead to neurodegenerative disease. At the root of the problem is a fundamental process: protein folding. . . . When proteins misfold, they can acquire alternative proteotoxic states [proteins becoming toxic] that seed a cascade of deleterious molecular events resulting in cellular dysfunction. When these events occur in neurons, the consequences can be devastating. . . . Collectively, these observations provide support for the hypothesis that graceful aging depends on the cell’s ability to counter the effects of stress by maintaining protein folding, which in turn permits appropriate protein function.
To understand the significance of protein folding and how it can go awry (leading to a variety of inherited and age-related diseases, not just neurodegenerative ones), you have to know a few things about proteins and how they fold.
The proper folding of proteins is indispensable to life as we know it. Understanding how it occurs could shed new light on some of the basic mechanisms of life and could pave the way for a better understanding of diseases and how to treat them. By the same token, understanding how protein folding can go awry through misfolding (incorrect folding) could illuminate many aspects of life, disease, and death, showing us how better to preserve life, prevent disease, and delay death.
Recall that a genetic mutation can lead to a protein with an abnormal primary structure and probably, therefore, an abnormal tertiary structure, which could cause disease. Similarly, misfolding in a normal protein’s tertiary structure could cause disease. Here’s another analogy: just as an error in the folding of an intricate origami figure could ruin the whole thing, a misfolding error in a protein could cause disease or death.
Misfolded proteins are implicated in a number of diseases, including cancer, cystic fibrosis, emphysema, chronic liver disease, hypercholesterolemia, nephrogenic diabetes insipidus, and a host of neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease), and Creutzfeldt-Jakob disease (the human analog of bovine spongiform encephalopathy, or mad cow disease). Because these diseases are due in part to protein misfolding—a pathological change in the protein’s conformation—they are called conformational disorders.
Chaperones. In our cells, molecular chaperones (also called heat-shock proteins) are specialized proteins that have evolved to help other proteins fold properly or to help stabilize or refold proteins that have become misfolded. By repairing the damage, the chaperones allow the proteins to regain their functionality. Without this vital cellular function, life as we know it could not exist.
Complementing molecular chaperones are chemical chaperones, which are small organic molecules that serve the same functions, albeit via different mechanisms. The confusing terminology is unfortunate, as the terms “molecular” and “chemical” are obviously relevant to both classes of chaperones. (There are also pharmacological chaperones, but let’s not get into that.)
There are two major classes of chemical chaperones, one of which is called osmolytes. Virtually all organisms have osmolytes in every cell, and they depend critically on them for protection against the damage caused by protein misfolding. Although most osmolytes, such as the amino acid proline, serve this protective role, some others have the opposite effect. Urea, for example, is an osmolyte, but it’s a protein denaturant, as we saw above.
Researches suggest that the preservation of Chaperones’ functionality while we age is closely associated with age related diseases and problems.
