Q J Med 2002; 95: 837-838
© 2002 Association of Physicians
Biologic |
Flat, folded or failed
Those who have not assembled a piece of previously flat-packed furniture are readily distinguished from the rest of the population at autopsy by the absence of scars on the pulp of the fingers. The curse of Ikea (a company founded by a now abstemious and reclusive Swede—are you surprised?) has fallen on many of us over the years and can be exorcized in places such as California by a fearless group of furniture assemblers who accept payment for risking their digits.
It is much harder with proteins. The primary, secondary and tertiary structure of proteins depends on sequence, site of assembly and processing, intra- or extra-cellular location and on physicochemical forces, with an elaborate system of controls and chaperones to determine form and function. The deposition of proteins that are normally soluble in tissues occurs when the mechanisms related to tertiary structure fail, and insoluble forms develop, giving rise to the amyloidoses. These now include Alzheimer's disease, variant Creutzfeldt-Jakob disease (vCJD) as well as the diseases that used to be called amyloid when I was a boy. The first transmissible form of this group of disorders to be identified was, of course, kuru—followed by what is now known as vCJD in young people given human-pituitary-derived growth hormone—then came BSE.
The deposits of proteins in all of these conditions are remarkably similar; they consist of thread-like fibrils, often assembled into masses and plaques and occurring in various tissues in amounts ranging from the microscopically detectable to kilograms. The fibrils are specific in type for each disease in the sense that each has a predominant protein component that is ‘reproducible’ from case to case—this may be a less specific finding than it appears in terms of pathogenesis, since it seems from recent work that all normally globular proteins may be persuaded to form fibrous amyloid structures in appropriate conditions. All the fibrils in the various types, however, can be assembled into a ß-pleated sheet (you can make one of these by folding a flat sheet of A4 paper about 1 cm from its shorter edge and repeating the process with the folds in opposing directions—not exact, but not a bad model). The sheets are produced by hydrogen bonding between the atoms of the main protein chain, something which is normally avoided by specific interactions of side-chains that are part of the structure-determining processes referred to above—processes that are essential to proper function.
If this is a universal model of protein failure, what is the process that has allowed it to develop over many millions of years? There are only 20 amino acids, and we produce around 50 000 proteins (average 300 residues each, but the code is redundant) all with a job to do, but all seemingly able to form amyloid. So why don't they all do it all the time? The correct tertiary structure of proteins is maintained only by the rigour with which the micro-environment of their active sites is controlled; the slightest unfolding of a tertiary structure will allow exposure of parts of the polypeptide chain to conditions that will allow hydrogen bonding and aggregation into fibrils. Material will then accumulate and prevent normal tissue function.
If there are mutant forms of a protein that are less stable than the ‘normal’ type under given conditions, their presence could be an adequate explanation for accumulation. Some variant proteins appear to behave in this way in some of the familial amyloidoses: for example, familial Mediterranean fever. In general, the age of onset of this group of diseases is thought to depend on the extent to which the mutation destabilizes the native protein. Dobson1 has suggested that in the dementias, the mutations might also increase the propensity of an incompletely folded protein to aggregate.
The transmissible amyloidoses (prion diseases) probably result from ingestion of prion proteins that have already aggregated; these aggregates then seed the process of plaque formation. Dobson believes that the reason that these diseases are becoming more common (apparently) is a mismatch between our extended life-span and our protein management capability; ageing wears out the machinery, just as with knees, DNA repair mechanisms in the skin and renal tubules. Most proteins only last a few weeks at most, but the lens lasts a very long time (though aggregates form as cataracts); it's the stability control that works. He suggests that Nature selects against old age—in fact, evolution is indifferent to post-reproductive failure and the idea that BSE (via vCJD) or kuru might exert selection pressure is a surprising one. However, most biological processes fail over time and the complex protein maintenance procedures are unlikely to be exceptional in this regard.
As these articles are always ‘asides’, let me make another detour. The hydrogen bonds referred to above in the establishment of the ß-pleated sheet are strong and irreversible. Much of the staining mythology of amyloid, once more important than the Nicene heresies to many pathologists, depends on this. In my final MRCPath viva, two fearsome Scottish pathologists, Professors Lennox and Lendrum, got into a row about a response of mine to a question on the staining of primary vs. secondary amyloid. They had argued about this for years at the Pathological Society meetings and proceeded to do so for 10 more minutes, ignoring me until a bell went and they told me I could go. I passed.
References
1. Dobson CM. Protein-misfolding diseases: getting out of shape. Nature2002; 418:729–30.[Medline]
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