Amyloids, prions and the inherent infectious nature of misfolded protein aggregates

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Misfolded aggregates present in amyloid fibrils are associated with various diseases known as ‘protein misfolding’ disorders. Among them, prion diseases are unique in that the pathology can be transmitted by an infectious process involving an unprecedented agent known as a ‘prion’. Prions are infectious proteins that can transmit biological information by propagating protein misfolding and aggregation. The molecular mechanism of prion conversion has a striking resemblance to the process of amyloid formation, suggesting that misfolded aggregates have an inherent ability to be transmissible. Intriguing recent data suggest that other protein misfolding disorders might also be transmitted by a prion-like infectious process.

Section snippets

Protein misfolding disorders

The biological function of cells depends on the correct folding of a network of thousands of proteins. The information required to fold a protein into a functional, specific three-dimensional structure is contained in its amino acid sequence. In general, proteins fold properly into their native conformation and, if they do not, the misfolding is corrected by chaperone proteins [1]. In protein misfolding disorders (PMDs), however, misfolding of a protein results in its aggregation and

The intriguing mechanism of prion diseases: an infectious protein

The crucial role of the protein misfolding process is perhaps most clear in the prion disorders [12], which are also called TSEs and are the only member of the PMD group known to be transmissible by infection. TSEs comprise a group of infectious neurodegenerative diseases that affect humans and other animals, and are characterized by brain vacuolation, astrogliosis, neuronal apoptosis and accumulation of the misfolded, protease-resistant prion protein (termed PrPSc) in the central nervous

The infectious nature of misfolded aggregates

Similar to the way in which PrPC is converted into PrPSc in TSE, the protein conformational changes associated with the pathogenesis of most PMDs result in the formation of abnormal proteins that are rich in β-sheet structure, are partially resistant to proteolysis, and have a high tendency to form larger-order aggregates 2, 3, 4, 5. Indeed, a common feature of several PMDs, including TSE, is the aggregation and deposition of the misfolded protein in different organs in the form of amyloid-like

Are other protein misfolding disorders infectious?

The transmissibility of amyloidosis and other PMDs has not been thoroughly investigated [31], but it is generally assumed, on the basis of epidemiological studies, that these disorders do not have an infectious origin. For example, family members or medical professionals working with individuals with PMDs do not have a higher propensity to develop the disease. The same is true, however, for prion diseases. It should be emphasized that the principles that generally apply to conventional

Alzheimer's disease

Several attempts have been made to transmit Alzheimer's disease to experimental animals with intriguing, but conflicting, results 36, 37, 38, 39, 40. Marmosets injected with brain homogenates from individuals with Alzheimer's disease developed scattered deposits of the amyloid-β protein (Aβ) in the brain parenchyma and cerebral vasculature 6–7 years after inoculation [41]. Interestingly, the resultant amyloid lesions were not limited to the injection site, but had spread well beyond into the

Concluding remarks

The important role of protein misfolding and aggregation in various human diseases has been clearly established in the past decade. Some of the most compelling studies come from TSEs, the only member of this group of diseases in which the pathology is naturally and experimentally transmitted among individuals by administration of the misfolded protein. The molecular mechanism underlying prion propagation is strikingly similar to the mechanism of amyloid formation, which suggests that disease

Acknowledgements

This work was supported, in part, by NIH grant NS549173.

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