Misfolded, clumping proteins evade conviction, but they remain prime suspects in neurodegenerative diseases
As open-and-shut cases go, Alzheimer's disease should top the list. The victim is clear. Suspects
are in custody. Wherever neurons die due to Alzheimer's disease, a protein known as amyloid-beta is always found at the scene of the crime, hanging around in large, tough gangs called plaques.
Parkinson's and Huntington's diseases; amyotrophic lateral sclerosis (which goes by its initials ALS or the alias Lou Gehrig's disease); and prion diseases, such as scrapie in sheep, mad cow disease in
cattle and Creutzfeldt-Jakob disease in humans, all have similar stories. Scientific investigators have pieced together this much: A seemingly mild-mannered brain protein falls in with a bad crowd, the
corrupted protein and its cronies gang up and mob violence results in the death of a brain cell. It's a scene repeated over and over again in different neighborhoods of the brain, by different proteins, but
all with the same result - the death of neurons and rise of disease.
But no one has convicted these suspected neuron killers. So far, cases mostly rely on circumstantial evidence, with large holes in the web of
proof. There's no smoking gun, no motive and no eyewitness to corroborate what scientists suspect. And there's no cure for the diseases that slowly break down brains and spinal cords, robbing
victims of memories or mobility.
No one has observed all the steps of a neuron's demise, so no one is sure exactly what the murder weapon is or who dealt the final blow. But scientists acting like
shamuses on the scent of a killer have picked up tantalizing clues about how neurons meet their end, and protein aggregation is almost certainly involved.
"It seems unlikely that coincidence is at
work here," says Bradley Hyman, a neurologist at HarvardMedical Schooland Massachusetts General Hospital-East in Charlestown, Mass.Recent research from Hyman and colleagues shows that plaques
develop more rapidly in the brains of mice prone to Alzheimer's disease than had been thought. The discovery, published February 7 in Nature, suggests that there may be many years between the appearance
of plaques and the onset of disease, providing a window of time for doctors to take action and stop the death of neurons.
Other researchers have recently reported progress on developing molecules
that may help protect the brain against proteins-gone-bad. And other new research shows that the perpetrator in some cases of neurodegenerative disease may not be one of the usual suspects.
The key to stopping the killing of neurons is figuring out what causes otherwise innocuous proteins to show their Mr. Hyde side, and discovering why the proteins flock together once they've turned. The
method by which "bad" proteins bump off neurons is also a matter of dispute. Scientists are drawing ever closer to solutions for these mysteries, and what they discover may one day help head off these
diseases or even repair some damage after rogue proteins have vandalized the brain or spinal cord.
Cause or effect
Not everyone believes that protein aggregation is such a bad thing for
neurons. Take those big plaques of amyloid-beta, or A-beta, found near dead and dying brain cells in Alzheimer's disease patients.
"Some people say it's a tombstone, others say it's not the cause,"
says Gang Yu, a neuroscientist and biochemist at the University of Texas Southwestern Medical Center at Dallas.
Big clusters of protein may be a cell's way of coping with otherwise harmful proteins,
suggests Lila Gierasch, a biophysical chemist at the University of Massachusetts Amherst. Plaques are "like garbage dumps for insoluble proteins," she says. Indeed A-beta plaques contain remnants of other proteins, perhaps dumped in the plaque to avoid cluttering up a cell
and gumming up its inner workings.
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