Sci. Aging Knowl. Environ., 20 April 2005
Sins of Synuclein
Chemical attachments turn Parkinson's protein into cell killer
As any makeover expert will attest, the wrong accessories can spoil even the most stylish outfit. But when a brain protein implicated in Parkinson's disease (PD) dons an extra chemical group, the result is worse than a fashion faux pas. The protein becomes poisonous, according to new research. The work also stokes a controversy in the PD field by suggesting that the protein knots that infest brain cells of patients are helpful--not harmful, as many scientists argue.
PD patients gradually lose muscle control as brain neurons perish, particularly cells that make the neurotransmitter dopamine (see Parkinson's Disease Case Study). Brain cells from these patients teem with snags of the protein -synuclein, and several lines of evidence incriminate the protein in the disease. For instance, people who make a particular version of -synuclein or carry extra copies of the -synuclein gene develop the rare inherited form of PD (see "The Goldilocks Genes"). Researchers aren't sure how -synuclein injures brain cells, but some data suggest that the addition of phosphate groups to the molecule makes it noxious. Another mystery is whether the -synuclein snarls are beneficial, harmful, or neutral. Neuroscientist Mel Feany of Harvard Medical School in Boston and her colleague Li Chen tackled both of these issues using fruit flies engineered to make -synuclein, a protein they don't normally manufacture (see "Flies Like Us").
Enzymes stitch phosphate onto -synuclein's 129th amino acid. In one group of flies, the researchers modified the protein at this position so that it carried a large negative charge, which chemically resembles a phosphate group. Brain cells died swiftly in these insects. But when Feany and Chen altered this amino acid so that the flies pumped out a version of the protein that can't receive phosphate, the bugs didn't lose neurons. Next, the researchers cranked up production of an enzyme that affixes phosphate groups to the 129th position of -synuclein. This meddling spurred rapid neuron die-off.
The researchers also determined whether phosphate attachment affected -synuclein clumping. They found that, compared to the negatively charged form, the phosphate-rebuffing protein was more likely to tangle. Moreover, flies that manufactured the phosphate-proof version carried more of the protein tangles than did the other insects. Combined with the toxicity observations, that finding indicates that the clots might protect brain cells rather than harm them. Overall, the results suggest that chemical modification "is key to controlling toxicity of -synuclein," says Feany. If globs of -synuclein do fend off brain deterioration, as the results imply, drugs under development to block formation of these clusters might be counterproductive, she says.
For several years, scientists have wondered whether added phosphate makes -synuclein dangerous, says neuroscientist Mark Cookson of the National Institute on Aging in Bethesda, Maryland, so this work is "the right experiment at the right time." He adds that researchers should now investigate whether addition of other chemical groups also affects the protein's toxicity. Prodding -synuclein to keep a clean, uncluttered look might be the best way to save brain cells.
April 20, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150