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Thursday, Feb. 13, 2003

NATURAL SELECTIONS

Ensuring age is the crown of life


The English scholar John Bailey said his wife Iris Murdoch, a prolific, perfectionist novelist and lecturer, became like "a very nice 3-year-old" as her Alzheimer's disease progressed. The disease made the proteins in her brain "misfold" and collapse, forming clots called amyloids that disrupt normal neurological function.

Misfolding proteins contribute to hundreds of human diseases, from Creutzfeldt-Jakob Disease (popularly known as Mad Cow Disease) to Parkinson's, Alzheimer's, Huntington's and cystic fibrosis. All are terrifying. And as we don't know exactly why proteins misfold, we certainly don't know how to cure these conditions.

But we might soon learn how to stop them misfolding.

Japan has one of the most rapidly aging societies in the world, and as the number of elderly people increase, so will the incidence of dementia.

According to the Health, Labor and Welfare Ministry, in 2000 there were 1.56 million Japanese with dementia; in 2025 there will be an estimated 3.15 million. The financial cost, not to mention the social cost, of caring for these people will likewise increase. How can we help those afflicted with dementia?

The amyloid diseases mentioned above are caused by proteins misfolding into a structure that makes them cluster together, forming microscopic fibril plaques.

The plaques, made up of hundreds of misfolded proteins, build up in internal organs and stop them from working properly, sometimes with lethal consequences.

Most previous approaches have aimed at preventing the misfolded proteins from conglomerating to form the hairlike fibril plaques, but now a new approach aims to prevent amyloid formation in the first place by stabilizing proteins in their native state.

Jeffery Kelly and colleagues in the department of chemistry at the Scripps Research Institute in La Jolla, Calif., are attempting to use small molecules to strengthen the proteins and keep them folded in their proper form.

Kelly and colleagues focused on a group of more than 80 rare amyloid diseases caused by the misfolding of the protein transthyretin (TTR). In these diseases, known as familial amyloid polyneuropathy (FAP), the liver secretes TTR into the bloodstream to carry thyroid hormone and vitamin A. Normally, TTR circulates in the blood as a "tetramer" made up of four separate protein subunits that bond to each other.

The protein subunits are made by two different genes. When one of the genes has a mutation, unstable tetramers form that are composed of mutant and normal subunits. Tetramers with mutant subunits often break up and misfold into the destructive amyloid fibrils.

These fibrils cause the disease FAP by building up around nerve and muscle tissue, disrupting their functions and leading to numbness, muscle weakness, and -- in advanced cases -- failure of the gastrointestinal tract.

The current treatment for FAP is drastic: a liver transplant. A healthy liver replaces the mutant gene with a normal copy.

Some therapies tried previously have involved administering drugs that inhibit the growth of fibrils from the misfolded state. This doesn't usually work because once an initial, misfolded fibril forms, it "seeds" the development of more fibrils and plaques form.

However, Kelly is confident that a designer molecule, what he calls a "suppressor subunit," can be used to increase the stability of at-risk proteins.

"The compound can be used prophylactically for individuals who have predisposing mutations," he said in an e-mail interview, "and it has been demonstrated that if one can slow the rate of misfolded protein accumulation there are mechanisms to clear the deposits, hence these compounds should be useful after the disease presentation."

Last year, Kelly and his colleagues discovered that suppressor subunits ameliorate disease by stabilizing the protein, thus preventing the disease-associated subunits from contributing to fibril formation. They found that even one such suppressor subunit incorporated into a tetramer otherwise composed of disease-associated subunits doubles its stability.

"The suppressor TTR subunits prevent misfolding by blocking tetramer dissociation accomplished by raising the barrier associated with this process," said Kelly.

"The same approach may also work with other amyloid diseases," added Kelly. "Any protein that misfolds and causes pathology that interacts with another protein, or has a small molecule-binding site, could, in principle, be targeted [with a small molecule to treat disease]."

Dementia used to be something people joked about; it was thought of as an inevitable consequence of aging. But not everyone gets it, and some people get it younger than others.

In Japan, the burden of care-giving falls on women. An Alzheimer's Association Japan report on dementia care in 2000 found that 64 percent of people with dementia are looked after at home by family members. Most family caregivers are daughters-in-law (28.9 percent), daughters (26.75 percent) and wives (16.5 percent). Clearly patients would not be the only ones to welcome possibilities offered by a new therapy.

But it is those at risk from dementia who could gain most from any future treatment. As Shakespeare has Dogberry lament of the old man Verges in "Much Ado About Nothing": "A good old man, sir; he will be talking: As they say, 'When the age is in, the wit is out: / God help us! It is a world to see.' "

It is a world to see, and would that we could leave it with the memories we have taken from it, not as nodding 3-year-olds.

The Alzheimer's Association Japan home page is at www2f.biglobe.ne.jp/~boke/boke2-e.htm Rowan Hooper welcomes comments at rowan.hooper@tcd.ie


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