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Protein folding diseases
Joachim Pietzsch
The process of protein folding is remarkably efficient, but sometimes it can go wrong. This can have harmful consequences, as the incorrect folding of proteins is thought to be the cause of diseases, such as Alzheimer�s disease and cancer.
For a long time, protein folding was regarded as simply a theoretical problem. Researchers investigated the mechanisms of protein folding to close the huge gap in our knowledge between the genetic blueprint of a protein and its biological function. Only in the 1990s did it become clear that wrongly folded proteins are involved in the development of many diseases. Now, protein folding has become a focus of attention in pharmaceutical research: it is probable that new approaches to the treatment of diseases such as cancer and Alzheimer�s disease are to be found within its convoluted pathways.
Protein folding diseases can be divided into two groups: in the first, excessive quantities of wrongly folded proteins collect in the form of uncontrolled piles of molecular rubbish. This is the group of diseases known as amyloidoses, of which Alzheimer�s disease is the best-known example. In the other, a small error in the genetic blueprint leads to incomplete folding of a protein, which affects its function. This might, for instance, happen to p53 � the malfunctioning of this central tumour suppressor could cause cancer.
Amyloidoses
The common characteristic of all amyloidoses is the collection of plaques of insoluble protein in the extracellular tissue, which cannot be broken down by enzymes. Their ordered structure gives them crystal-like properties: they are made up of long filaments (fibrils) that are formed from densely packed b
-pleated sheets of identical proteins. There are about 20 different proteins that can act as the building blocks of these fibrils, each of which is associated with a different disease. In so-called systemic amyloidoses, the precursors of these plaques are transported through the bloodstream from their point of origin to their point of deposition. Localized amyloidoses are of greater clinical significance, as they mainly affect the central nervous system, the extracellular tissue of which is particularly susceptible to damage.
Alzheimer�s disease
One of the main characteristics of Alzheimer�s disease is the accumulation of plaques of insoluble b-amyloid in the brain. It is still not certain whether these plaques are a cause or a consequence of the disease, but there is a lot of evidence for the former being the case. The b-amyloid plaques are formed by cleavage of amyloid-precursor protein (APP) by two different enzymatic activities, which release amyloid-b peptide fragments that are 40 or 42 amino acids long (Fig. 1). These then form fibrils, which aggregate into insoluble clumps of b-amyloid plaques that surround neurons and might cause damage.
But this cleavage also occurs in healthy individuals and soluble b-amyloid proteins are normal constituents of brain tissue. How, then, do the plaques form in Alzheimer�s patients? It is thought that the misfolding of the protein dramatically alters its properties. In the normal protein, hydrophobic (water-repelling) amino acids bury themselves inside the protein right from the start of folding. However, if the protein folds wrongly, these hydrophobic amino acids are exposed and they rapidly seek out and bind to hydrophobic groups on other protein molecules, forming the insoluble aggregates or plaques that are found in Alzheimer�s patients.
Prion diseases
Transmissable spongiform encephalopathies (TSEs), which include mad cow disease (bovine spongiform encephalopathy; BSE) and Creutzfeld�Jakob disease (CJD) in humans, are special forms of amyloidosis in which the victim�s brain degenerates to a structure that looks like a porous sponge. These conditions seem to occur when normal human protein particles called prions misfold. The normal human prion is a component of the membrane of healthy nerve cells (called PrPc), which folds properly, remains soluble and is disposed of without problem. It can, however, misfold in a particular way, which allows it to take on an infectious, incorrectly folded three-dimensional form (called PrPsc), presumably due to a genetic mutation. The infectious prion, which can be transmitted in the diet, triggers a domino effect in healthy prions, forcing them to adopt its incorrectly folded form (Fig. 2).
Misfolding and cancer
Whereas too much of an incorrectly folded protein can cause amyloidoses, another group of protein folding diseases is caused by lack of a correctly folded protein. This form of protein folding defect is thought to be involved in diseases such as cystic fibrosis, but mainly affects a protein called p53, which occupies the most important position in the body�s cancer resistance network. Normally, the p53 system is switched off or, at most, is in stand-by mode. It is activated inside a cell if the cell becomes excessively stressed or damaged, which can lead to genetic mutations in DNA that can cause the uncontrolled division and proliferation of cells that is the hallmark of tumour formation. p53 is so good at its job that even a single break in the DNA strand is enough to activate it. It rushes into the cell nucleus and induces the production of other proteins that stop uncontrolled cell division or trigger the programmed death of a cell (Fig. 3).
This tumour-suppressing function of p53 is so important that the protein has been described as the �guardian of the genome�. So, it is no surprise that faults in the p53 gene can be disastrous. Even a mutation in one of the letters (nucleotides) in the gene can be enough to lead to the expression of p53 proteins that do not fold correctly. Half crippled, they cannot carry out their job properly, so the damage to the DNA that would normally be repaired goes unnoticed, allowing the abnormal cell to grow in an uncontrolled manner. This type of mutation in p53 is thought to occur in 50% of all cases of cancer and as many as 95% of all cases of lung cancer. |
