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Instant insight: Think outside the cell
20 December 2007
Mark Wilson and Justin Yerbury at the University of Wollongong, Australia, examine proteins' extracellular activities
Proteins perform many different functions critical for life, from building our muscle structure to digesting our food. These large biological molecules each have a unique three-dimensional shape which they require to perform their function. In protein deposition diseases (PDDs), however, a disease-specific protein molecule unfolds from its normal shape and assembles together with like molecules into insoluble rod-shaped fibrils. These protein deposits can be found in the brain, skeletal tissue and various organs; in some cases they may become large enough to disrupt tissue structure and function.
One of the most prevalent and costly PDDs is Alzheimer's disease, but there are more than forty diseases in this group, including Parkinson's disease, bovine spongiform encephalopathy, or 'mad cow' disease, and motor neurone disease. When it is considered that cells and their surrounds (extracellular spaces) are densely packed with thousands of different proteins, and are exposed to many stresses capable of unfolding proteins, it seems miraculous that there are not more of these PDDs.
In diseases such as Alzheimer's, proteins can form rod-shaped deposits in the brain
Inside cells - intracellularly - a large amount of energy is invested into ensuring that proteins reach and maintain their normal (native) shape. This quality control machinery includes molecular chaperones, which bind to hydrophobic regions normally buried inside the native shape of a protein, and sophisticated degradation machinery such as the proteasome. There is little doubt that these intracellular mechanisms protect our bodies from PDDs that would otherwise produce harmful protein deposits inside cells. But what happens outside cells where many PDDs, including Alzheimer's disease, produce insoluble deposits? Very little previous work has examined this question, being instead directed towards those now relatively well understood intracellular mechanisms.
Studies of the system(s) sensing and controlling protein folding in extracellular spaces of the body are still in their infancy but in time are likely to produce important insights into the mechanisms underpinning extracellular PDDs. These insights will provide new opportunities to develop therapeutic strategies for a range of diseases that will have an increasing impact on an ageing world population.
Read Wilson et al's review 'Potential roles of abundant extracellular chaperones in the control of amyloid formation and toxicity' in Molecular BioSystems.
Mark Wilson's Homepage
Mark Wilson's Homepage at the University of Wollongong
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Link to journal article
Potential roles of abundant extracellular chaperones in the control of amyloid formation and toxicity
Mark R. Wilson, Justin J. Yerbury and Stephen Poon, Mol. BioSyst., 2008, 4, 42
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