Amyloids, Prions & the Infectious Misfolded Protein Aggregates

Amyloids, Prions & the Infectious Misfolded Protein Aggregates

By March 6, 2006 No Comments

Originally Posted on Trends in Biomedical Sciences | March 2006

scientist researching on Infectious Misfolded Protein

Infectious misfolded protein aggregates present in amyloids 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 infectious misfolded protein 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 diseases might also be transmitted by a prion-like infectious process.

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.In protein misfolding disorders (PMDs), however, misfolding of a protein results in its aggregation and accumulation as protein deposits in diverse tissues.

Among the PMDs are Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, transmissible spongiform encephalopathies (TSEs), serpin-deficiency disorders, hemolytic anemia, cystic fibrosis, diabetes type II, amyotrophic lateral sclerosis, secondary amyloidosis, dialysis-related amyloidosis and more than ten other rare diseases. Although the proteins involved in these diseases do not share sequence or structural identity, all of them can adopt at least two different conformations without requiring changes in their amino acid sequence. The misfolded form of the protein usually contains stacks of b sheets organized in a polymeric arrangement known as a ‘cross-b’ structure. Because b sheets can be stabilized by intermolecular interactions, misfolded proteins have a high tendency to form oligomers and larger polymers.

Compelling data from biochemical, genetic and neuro-pathological studies support the involvement of protein misfolding and aggregation in the pathology of PMDs. For example, abnormal aggregates are usually present in the tissues with most damage, and accumulation of these deposits in diverse organs is the endpoint in most PMDs. Mutations in the gene encoding the misfolded protein produce inherited forms of the disease, which usually have an earlier onset and a more severe phenotype than the sporadic forms. Transgenic animals expres-sing a human mutant gene for the misfolded protein develop some of the neuropathological and clinical characteristics typical of the human disease. Finally, misfolded protein aggregates produced in vitro are toxic to cells and induce apoptosis.

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