Your fate can be determined by tiny events. Imagine you live in the city and you walk everywhere to get exercise - you are healthy and not afraid of getting mugged. You almost never eat breakfast so you don't stop at the donut shop on the way to work, until one day the manager replaces the girl at the counter with her pretty red-haired younger sister. This seemingly unimportant change in your world is just enough to overcome your ability to resist high-fat temptation. A million donuts later, your cholesterol level surges and then your heart gives out. Curse you, little red-haired girl!
Like staff change at the donut shop, subtle, seemingly inconsequential differences in human genetic design can lead to some unexpected tipping points in cellular chemistry that can lead to disaster. Cellular processes, like all the routines of life, are unfathomably complex, constantly evolving, and are sometimes dramatically sensitive to the smallest of changes. Consider the case of Alzheimer's disease…
Alzheimer's is a terrifying brain-destroying disease whose causes have proven very difficult to pin down. In recent years, science has been closing in on solving the puzzle, particularly regarding some of the hereditary, "early onset" forms of the illness. Unusual by-products of cell metabolism, clumps of protein aggregates, have been shown to have a toxic effect on brain cells and certain gene mutations have been shown to be associated with increasing production of these by-products, though the evidence for an exact mechanism has remained hidden.
Now, using sophisticated computer simulations, a team of physical chemists have shown precisely how a minor, seemingly inconsequential mutation results in unexpected changes in a very delicate chemical balance, creating build-up of the toxic by-products.
The mutation, the substitution of a single base among the 3 billion found in human DNA, seems to have the greatest effect on a fragment of a specific protein that is abundantly present in living cells. The difference causes a subtle change in the shape of the fragment at a critical point, which can slightly shift the odds towards an inappropriate biochemical reaction that sidetracks the metabolic path. The increase in the reaction simply tips the balance of chemical processes, causing the build-up of a substance that kills brain cells, leading to the early deterioration of mental capacity and, eventually, death.
"It is a really tiny change but it has tremendous consequences," said Andrij Baumketner, lead author on the study and a faculty member in the department of physics and optical science at the University of North Carolina at Charlotte. The finding, published in the April 7 issue of the Publication of the National Academy of Sciences, was co-authored by Mary Griffin Krone and Joan-Emma Shea, both from the department of chemistry and biochemistry at the University of California at Santa Barbara.
The group studied the effects caused by the Dutch Mutation, a mutation that has been discovered to be associated with a specific, hereditary form of Alzheimer's disease. The mutation is small, the simple substitution of one DNA base for another, resulting in the change of only one amino acid residue - glutamic acid changing to the very similar glutamine - among hundreds of amino acids that form a protein known as the amyloid precursor protein (APP). The greatest effect of the Dutch-type mutation on APP, whose primary biological function is unknown, seems to be through a fragment known as amyloid-beta peptide that is created when cells break down the protein. Studies have shown that mutated forms of the fragment have greater tendency to stick to bond together and form protein clumps or aggregates. Some forms of the amyloid-beta clumps have been shown to be toxic to brain cells.
Why the change in one amino acid would cause this peptide to form clumps more readily has, until now, been unclear. Amyloid-beta peptide, unlike most other proteins present in the cell, is largely lacking in specific shape (conformation), the characteristic that usually controls how proteins interact with each other. However the fragment does have two places in its sequence of amino acids - a section known as the "bend" and an area known as the "central hydrophobic cluster" where the polypeptide chain does conform to a more-or-less fixed shape. These areas, in fact, seem to be involved when the fragments bond together into clumps.