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.

Recently, it was discovered that a small group of human blood proteins are able to chaperone misfolded proteins, keeping them soluble and inhibiting their aggregation. Each of these extracellular chaperones - clusterin, haptoglobin and alpha₂-macroglobulin - is bound by specific cell surface receptors that can internalise them and their ligands for subsequent degradation inside the cell. So the extracellular chaperones and their receptors may comprise the foundation of an extracellular system for protein folding quality control, a system that may be overwhelmed in extracellular PDDs such as Alzheimer's disease. Consistent with this proposal, extracellular amyloid-beta peptide (which forms the plaques in the brain in Alzheimer's disease) is cleared from mouse brains much faster when it is bound to clusterin and slower when alpha₂-macroglobulin or the alpha₂-macroglobulin receptor are inhibited.

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.