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beta-sheets

Tuesday 24 January 2006

Pathogenesis

Although the molecular mechanisms involved are diverse and characteristic of each disease, almost all result in beta-linkages formed by hydrogen bonding between peptide loops and sheets.

Some larger, highly ordered proteins, such as the cystatins, can form intermolecular linkages by domain swapping, as with the loop-sheet linkages of the serpins. The result is the formation of polymers in which the individual molecules substantially retain their ordered structure.

In other proteins, such as beta2-microglobulin, lysozyme and transthyretin, linkage occurs by the remarkable realignment of peptide segments to give the sequential layering of beta-structures known as amyloid.

The characteristic features of amyloid are its staining with the dye Congo red and its birefringence to polarized light.

The determinant feature of amyloid is the formation of a specific pattern on X-ray diffraction, which has been interpreted as being due to the formation of layered arrays of extended beta-sheets.

Amyloid is most frequently observed as large tissue or pericellular deposits; in several systemic amyloidoses this end product interferes with organ function (for example, in the heart, lung or liver) and so is directly responsible for the disease pathology.

The dementias, however, arise specifically from the cumulative loss of neurons, and the pathology is likely to occur directly at the cellular level.

- Attention is therefore focused on the earliest forms of intracellular association, at the level of fibrils and oligomeric fibrillization intermediates (protofibrils), as well as the preceding dimers and oligomers.

The oligomers also have a predominantly beta-sheet structure and this change in structure underlies neurotoxicity.

- This is underscored by studies of mutants of alpha-synuclein (SNCA), a highly conserved protein of 140 amino acids that is expressed predominantly in neurons and is particularly abundant in presynaptic terminals.

It has been suggested that it might have a role in synaptic plasticity and might modulate DOPAMINERGIC neuro-transmission.

Two amino-acid substitutions in alpha-synuclein, A53T and A30P, are associated with autosomal-dominant, early-onset Parkinson disease. The mutant protein accumulates as intracytoplasmic inclusions in neurons to form the Lewy bodies that are characteristic of this condition.

Structural studies have shown that the A30P mutant favours the formation of oligomers rather than fibrils, and that these small intermediates could be the toxic species that cause cell death and the associated neurodegenerative disease.

References

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