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Tuesday 24 January 2006


- Propagation and prions

Structural studies of the serpins have shown the feasibility of another perplexing feature of some of the familial and acquired encephalopathies: the ability of the underlying protein oligomers and filaments to self-propagate and even, with the prions, to propagate infectively.

Aggregation to form polymeric filaments is particularly likely to occur when there is a beta-strand receptor, as in the main beta-sheet of the conformationally unstable variants of alpha1-antitrypsin.

Both the serpins and the prions readily dimerize by domain swapping, and the initial oligomers, like those formed by serpins, act as a template for propagation of the conformational change.

The change is propagated from molecule to molecule, which then extend to give long-chain polymers. This is well illustrated by mutations of antithrombin.

Whereas mutations in alpha1-antitrypsin and neuroserpin result in the formation of long-chain polymers, those in antithrombin result in the formation of an inactive antithrombin monomer.

Moreover, in a process similar to that proposed for the prion encephalopathies, this aberrant form of antithrombin then binds to a normal antithrombin molecule, which leads to the propagation of conformational inactivation.

A more direct insight into the mechanisms of prion propagation that underlie the spongiform encephalopathies is provided by studies of the unrelated yeast prion Ure2. This normally soluble and highly ordered molecule undergoes a conformational change to form fibrils that bind the dye Congo red and show typical amyloid-like birefringence.

However, these fibrils do not have the cross-beta-structure of amyloid and, as is also observed with fibrils formed by orderly aggregation of serpins, the component molecules of the fibril retain their helical structure.

These amyloid-like fibrils are self-propagating but lose this ability over time, coincident with a transition of the fibril to give the typical amyloid X-ray fibre diffraction pattern.

These findings fit with a range of others and together they indicate that the neuronal pathology of the conformational dementias results from the early stages of intracellular aggregation, before or incidental to amyloid formation.


- Lomas DA, Carrell RW. Serpinopathies and the conformational dementias. Nat Rev Genet. 2002 Oct;3(10):759-68. PMID: 12360234