Thursday, June 17, 2010

shock and age

The Scientist | The accumulation of misfolded protein marks the accrual of years as the body ages. Could heat shock proteins be used to reduce the effects of aging and diminish the risk of disease by untangling improperly folded proteins?

What does a molecular thermometer look like? This seemed to be a simple question, not much different from the many science fair projects I had done in grade school and high school in Chicago. But rather than the simple solutions I’d present on triptych posterboards, the answer to this question has kept me fascinated for my entire career. The cell’s thermometer appears to be a network of stress-sensing transcription factors and specialized proteins—molecular chaperones—that function as the guardian of the proteome, sensing damage and keeping the cell’s proteins properly folded as they roll off the production line of ribosomes. Exciting as that was, none of us working on this question at the time could have predicted that this thermometer might also control the body’s fountain of youth and provide new ways of thinking about disease.

Proteins are fundamental building blocks for the cell; they are the predominant products of the genome that provide much of the shape and functionality of cells, tissues, and organisms. The proper synthesis, folding, assembly, translocation, and clearance of proteins is essential for the health of the cell and the organism. Proteins also provide the essential parts to replenish molecular machines for biosynthetic processes and ensure their efficient functioning in the adult cell, a process critical for longevity. At the root of the problem is a fundamental process: protein folding. When quality control—as overseen by heat shock proteins and molecular chaperones—slips, errors occur and persist. This interferes with molecular processes, which can lead to disease. When these events occur in neurons, the consequences can be devastating, leading to major classes of neurological disorders, like multiple sclerosis, Huntington’s disease, Parkinson’s disease, and Alzheimer’s disease.