Brain 'traffic jams' drive Parkinson's symptoms
Stopping cellular tailbacks could speed the way to therapies.
Using a zoo of animals from yeast to rats, US scientists have shown that speeding the flow of proteins in cells might relieve one of the underlying causes of Parkinson's disease.
During the disease, brain neurons that make the chemical dopamine wither and die, causing the movement problems that characterize Parkinson's. The condition affects around 1% of people aged over 60.
Researchers don't know exactly what causes the dopamine-making neurons to fail, but they have found that these cells accumulate hallmark clumps of proteins, including one called -synuclein.
Researchers at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, turned to yeast to find out what ?-synuclein actually does, despite the fact that yeast, as a single-celled organism, is an unlikely model for a complex brain disease. "A lot of people thought we were crazy," says lab head Susan Lindquist. "We've gone a long way to showing it's not crazy and it's actually really promising."
Three years ago, Lindquist and her colleagues engineered yeast cells to produce human -synuclein. They found that yeast cells making too much of this protein sicken and die, much like affected brain cells1.
Now the team has found a way to stop the yeast cells dying. Overcoming the build-up of -synuclein with a future drug, they hope, might also prevent or relieve the symptoms of Parkinson's in patients.
The researchers showed that, within hours of switching on -synuclein in yeast cells, small sacs of proteins stop shuttling normally between two compartments of the cell called the endoplasmic reticulum (ER) and the Golgi apparatus. This transport is vital for the cell to process and deliver all its proteins to their correct destinations. The researchers report their discovery in Science2.
Next, Lindquist and her colleagues searched for a way to override this problem. They engineered more than 3,000 yeast strains so that each one made a lethal overdose of -synuclein, and an excess of one other protein.
They pulled out 34 strains in which the overproduction of one protein seemed to compensate for problems with -synuclein. Many of these appear to boost transport between the ER and Golgi apparatus, and presumably overcome the hold-up caused by -synuclein.
The team focussed on one seemingly therapeutic protein, called Rab1. They showed that delivering extra quantities of this protein can block the decline of dopamine-making neurons in worms, flies and in rat neurons grown in the laboratory.
The researchers suggest that people who develop Parkinson's disease may do so partly because their -synuclein goes awry, causing knock-on effects for the transport of all protein-containing sacs in the cell. This could affect every cell in the body, but the idea is that dopamine-making neurons fail first because the chemical is toxic if it isn't contained efficiently in sacs.
The discovery could point the way to new drugs. Lindquist's colleague Aaron Gitler says that the team has already screened several thousand chemicals to find compounds that can also block the toxic accumulation of -synuclein in yeast, and found two or three that work and might provide a starting point for human therapies.
The researchers still don't know why -synuclein goes wrong in the first place; it could be a combination of many different things in different people, including a person's genes and a lifetime of wear and tear on cells.
And problems with -synuclein are unlikely to be the whole story. Scientists have linked a handful of other proteins and cellular processes to the disease, such as defects in the removal of waste proteins and in energy-making mitochondria.
Next it would be nice to find out whether Rab1 can also correct problems with these other defective proteins, says Alex Whitworth, who studies the disease using flies at the University of Sheffield, UK. "That would really flag it as being central to the disease," he says.
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- Outeiro T. F.& Lindquist S. Science, 302. 1772 - 1775 (2003).
- Cooper A. A., et al. Science, 10.1126/science.1129462 (2006).