Trends in Biochemical Sciences
Amyloids, prions and the inherent infectious nature of misfolded protein aggregates
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.
References (71)
Alternative conformations of amyloidogenic proteins govern their behavior
Curr. Opin. Struct. Biol.
(1996)- et al.
Conformational disease
Lancet
(1997) Protein misfolding, evolution and disease
Trends Biochem. Sci.
(1999)Protein misfolding and disease; protein refolding and therapy
FEBS Lett.
(2001)- et al.
Review: history of the amyloid fibril
J. Struct. Biol.
(2000) - et al.
Prions: disease propagation and disease therapy by conformational transmission
Trends Mol. Med.
(2001) Variant Creutzfeldt–Jakob disease
Lancet
(1999)In vitro generation of infectious scrapie prions
Cell
(2005)Degeneration of skeletal muscle, peripheral nerves, and the central nervous system in transgenic mice overexpressing wild-type prion proteins
Cell
(1994)Neurological illness in transgenic mice expressing a prion protein with an insertional mutation
Neuron
(1998)