Sci. Aging Knowl. Environ., 1 June 2005
Vol. 2005, Issue 22, p. nf40
[DOI: 10.1126/sageke.2005.22.nf40]


Ties That Bind the Brain

Parkin and glutathione deficits slay dopamine-producing neurons in flies

R. John Davenport

To expose mob scams and shady corporations, investigators must make connections between key wrongdoers. Now, researchers have linked two perpetrators that contribute to Parkinson's disease (PD). A defect in an antioxidant system that doesn't by itself cause trouble for flies exacerbates neuron loss in insects with a PD-associated mutation. The findings suggest that PD arises when antioxidants can't counteract mounting protein damage.

In PD, dopamine-producing neurons perish when they fill with protein clumps called Lewy bodies, hampering muscle control (see Parkinson's Disease Case Study). Most PD cases arise randomly, but rare inherited forms result from genetic flaws. For instance, mutations that cripple a gene called parkin trigger a version of PD that strikes before age 40. Some studies have suggested that the protein Parkin might also contribute to sporadic PD. The protein marks damaged proteins for disposal, and if it malfunctions, they might accumulate and gather into Lewy bodies.

To probe how Parkin kills brain cells, geneticist Leo Pallanck of the University of Washington, Seattle, and colleagues generated fruit fly lines that lack parkin. Previously, the team had found that such flies climb clumsily, a sign of muscle deterioration. Dopamine-producing neurons, however, seemed to remain intact (see Trojanowski and Lee Perspective). In the new study, the researchers used a more sensitive method to track cell death. They engineered dopamine-producing neurons to make a fluorescent protein and then scrutinized whole fly brains with a confocal microscope. Parkin-deficient flies lost cells from one particular cluster of neurons. In 20-day-old insects--roughly middle-aged for a fly--one-third of the neurons in this group had perished.

Next, the researchers sought molecules that enhance the parkin defect. Genetic flaws in an enzyme called GstS1 worsened the climbing difficulties in Parkin-deficient insects and spurred more neurons to expire. Flies with faulty GstS1 alone scaled tubes normally and didn't lose brain cells. Furthermore, generating extra GstS1 in the Parkin-lacking flies improved climbing and protected neurons. GstS1 knits the antioxidant glutathione onto proteins, protecting them from damage, and it might reduce the number of oxidized proteins that accrue when Parkin falters, says Pallanck. Other scientists have observed that brains of PD patients lose glutathione, he adds, so drugs that crank up glutathione quantities might help alleviate PD.

The work is "very exciting," says PD researcher Julie Andersen of the Buck Institute for Age Research in Novato, California. It "ties together two important [but previously unrelated] factors in late-onset, sporadic PD": defective protein degradation and loss of glutathione. To understand how the fly findings apply to PD, researchers should determine whether the affected insect neurons correspond to the cells lost in human PD brains. Neuroscientist Ted Dawson of Johns Hopkins University in Baltimore, Maryland, praises the study for its improved method of analyzing fly neurons. Experiments with flies carrying a PD-linked alteration in another gene originally revealed neuron loss, but subsequent studies using the confocal approach questioned that finding. The new technique overcomes sample preparation problems that confound the older approach, he says. Further studies should provide more intelligence into coordinated efforts that victimize aging brains.

June 1, 2005
  1. A. J. Whitworth et al., Increased glutathione S-transferase activity rescues dopaminergic neuron loss in a Drosophila model of Parkinson's disease. Proc. Natl. Acad. Sci. U.S.A., 23 May 2005 [e-pub ahead of print]. doi:10.1073/pnas.0501078102 [Abstract/Free Full Text]
Citation: R. J. Davenport, Ties That Bind the Brain. Sci. Aging Knowl. Environ. 2005 (22), nf40 (2005).

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