conformational dementias

Past studies of the molecular-genetic basis of disease have focused on mutations that cause either the deficiency or the inactivity of a protein.

More recently, however, it has been realized that many diseases arise from mutations that primarily affect neither expression nor function, but result in a protein with decreased conformational stability.

This conformational instability can intermittently cause the affected protein to unfold and then undergo intermolecular linkage, which results in intracellular aggregation that causes cumulative cell damage.

The insidious nature of protein accumulation explains why some familial diseases characteristically affect individuals in middle- or old-age.

The aggregation of conformationally destabilized proteins is now known to be a feature of many of the neurodegenerative diseases, notably of Alzheimer disease and Parkinson disease and the spongiform encephalopathies.

The common consequence of the mutations in all these diseases is the molecular instability of the encoded protein, which results in the formation of intermolecular linkages, in which single peptide strands become aligned to form highly stable beta-shhets. These -linked structures then accumulate to cause cell death and hence disease.

Classification

 late-onset dementia
 amyloidoses
 prion encephalopathies
 Huntington disease
 Alzheimer disease
 FENIB

Pathogenesis

 Polymers and amyloid

The shared feature of the conformational dementias is the formation of intermolecular linkages with resultant protein aggregation.

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.

 However, 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.

 alpha-synuclein mutations and early-onset Parkinson disease

This is underscored by studies of mutants of alpha-synuclein, 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.

 Serpinopathies

The serpin family of protease inhibitors provides an unexpected model of the way in which mutations that are present from birth might only result in disease much later in life. The studies of the serpins show not only how aberrant -linkage can result in polymerization, but also, more recently, how these intermolecular linkages can be prevented or reversed.

Mutations in the strongly conserved region at the commencement of the B-helix in alpha1-antitrypsin ( PI ), neuroserpin, antithrombin, C1 inhibitor and alpha1-antichymotrypsin all result in polymerization and disease.

References

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