Sci. Aging Knowl. Environ., 22 June 2005
Vol. 2005, Issue 25, p. nf46
[DOI: 10.1126/sageke.2005.25.nf46]


Sticking It to Parkinson's Disease

Vaccination spares mice from brain damage

Mitch Leslie

Vaccines have subdued once-dreaded killers such as polio and smallpox, and new research suggests they might help battle Parkinson's disease as well. Mice receiving shots containing a protein that accumulates in Parkinson's disease (PD) suffered less brain deterioration, suggesting a possible new means for fighting the incurable neurodegenerative illness.

PD patients suffer tremors and rigid muscles as brain cells that supply the neurotransmitter dopamine perish (see "Parkinson's Disease Case Study"). Researchers haven't pinned down what causes this attrition, but a leading suspect is the protein {alpha}-synuclein. In PD and a related brain-scarring disease, knots of abnormally folded {alpha}-synuclein build up inside neurons. Vaccines can stem the accumulation of Alzheimer's disease plaques in rodents, so neuroscientist Dale Schenk of Elan Pharmaceuticals in South San Francisco, California, and colleagues tried inoculating mice with {alpha}-synuclein.

For 8 months, the team gave mice engineered to accumulate human {alpha}-synuclein regular injections of the protein. The shots spurred the rodents to pump out antibodies against {alpha}-synuclein. Brains from vaccinated mice carried fewer protein clots than did rodents that had received a control shot. Some animals produced antibodies that gripped {alpha}-synuclein particularly tightly, and these rodents sported fewer clumps than did animals with less clingy antibodies. Mice that received an inert shot lost 20% of the cells in one brain region. Rodents that received {alpha}-synuclein harbored normal quantities of the neurons, suggesting that the injections protect against brain deterioration.

Three years ago, researchers stopped trials of an experimental vaccine against Alzheimer's disease when several patients developed severe brain inflammation. To gauge whether {alpha}-synuclein shots might trigger a similar problem, Schenk and colleagues measured the quantities of two proteins carried by activated brain immune cells. Both rose slightly in the vaccinated animals, suggesting that the injection sparked only a mild immune reaction, says Schenk. To probe how the injections break down {alpha}-synuclein, the team dosed the mice's brain tissue with two kinds of glowing antibodies, one that tags {alpha}-synuclein and one that latches onto the lysosome, an organelle that minces worn-out proteins. The two kinds of antibodies bunched together, suggesting that the vaccinations spur formation of antibodies against {alpha}-synuclein that prod cells to dispatch the protein to lysosomes for destruction.

"This is an innovative and interesting approach and a good first step," says neuroscientist Howard Gendelman of the University of Nebraska Medical Center in Omaha. But obstacles block the road to a treatment, he cautions. In particular, by the time of diagnosis, the average PD patient has lost 50% to 70% of dopamine-producing neurons. Vaccinations might have to begin early to overcome such severe damage. We need to learn more about {alpha}-synuclein's jobs before we can be sure that targeting it is wise, adds neuroscientist Julie Andersen of the Buck Institute for Age Research in Novato, California. But even if this strategy doesn't lead to a new treatment, she notes, the vaccine might help answer a burning question in PD research: whether the clumps of {alpha}-synuclein are harmful, beneficial, or neutral. Further work might reveal whether vaccines can shoot down PD.

June 22, 2005
  1. E. Masliah et al., Effects of {alpha}-synuclein immunization in a mouse model of Parkinson's disease. Neuron 46, 857-868 (2005). doi:10.1016/j.neuron.2005.05.010 [CrossRef][Medline]
Citation: M. Leslie, Sticking It to Parkinson's Disease. Sci. Aging Knowl. Environ. 2005 (25), nf46 (2005).

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