Sci. Aging Knowl. Environ., 7 September 2005
No Parkin Zone
Researchers nab possible cell killer in Parkinson's disease
Like a kid who misbehaves while her mother naps, a protein might run amok when cellular supervision wanes, triggering Parkinson's disease (PD). According to new work, quantities of the protein soar when another molecule that normally keeps it in check falters. The study suggests a new way to stanch the loss of brain cells in PD.
PD patients suffer symptoms such as tremors and rigid muscles because brain neurons that manufacture the neurotransmitter dopamine die (see Parkinson's Disease Case Study). To protect these cells, researchers want to collar their killer. Some evidence implicates flaws in a protein called parkin (see "Ties That Bind the Brain"). It affixes the molecule ubiquitin to other proteins, which dispatches them to the proteasome, the cell's trash incinerator (see Gray Perspective). About half of patients with the inherited--and rare--form of PD carry glitches in parkin. Moreover, some studies suggest that parkin goes awry in the nongenetic type of PD. In this more common form, molecules of nitric oxide can glom onto the protein and shut it down. Researchers hypothesize that one of the proteins that parkin normally sends to the proteasome piles up, killing cells. Although scientists have identified several molecules that parkin condemns, they don't know if any accumulate in PD.
To winnow the suspects, neuroscientist Ted Dawson of Johns Hopkins University School of Medicine in Baltimore, Maryland, and colleagues measured quantities of parkin targets in the brains of mice that lack parkin. They found increased amounts of only one, a protein called p38. Moreover, brain tissue from patients with PD harbored surplus p38, suggesting that faulty or missing parkin allows the protein to accumulate. To determine whether the buildup is harmful, the researchers engineered human nerve tumor cells to produce extra p38. The alteration tripled the cells' death rate. Injecting a virus carrying p38 into the brains of parkin-devoid mice spurred dopamine neurons to generate p38 and boosted the number of dying cells. Together, the results suggest that rising amounts of p38 help incite the PD-related cell die-off, says Dawson. Why parkin normally reins in p38 is uncertain, he says. Parkin could be regulating the amount of working p38 in the cell, or it could be eliminating damaged p38. In either case, drugs that prevent excess p38 from doing harm might save brain cells in PD patients, Dawson adds.
The study makes a strong case that p38 is parkin's target in cells, says neuroscientist Mark Cookson of the National Institute on Aging in Bethesda, Maryland. He lauds the work for evaluating multiple candidate molecules instead of focusing on one, as other studies have done. However, the results don't rule out these proteins, cautions neuroscientist Leonard Petrucelli of the Mayo Clinic in Jacksonville, Florida. He notes that the researchers found elevated p38 even in brain areas that don't lose cells in PD, suggesting that the protein needs help to kill. Both scientists concur that the next step is determining how p38 spurs cell death. The answer might reveal whether keeping p38 in line will help neurons survive.
September 7, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150