Sci. Aging Knowl. Environ., 12 March 2003
Vol. 2003, Issue 10, p. nw41
[DOI: 10.1126/sageke.2003.10.nw41]


Death Be Not Degrading

Parkinson's protein trashes cell-suicide protein to block neuron death

R. John Davenport;2003/10/nw41

Key Words: ubiquitin ligase • cyclin-dependent kinase • excitotoxin

Our companions can reveal a lot about our behavior--and that's true for proteins as well as people. New work uncovers collaborators of a protein implicated in Parkinson's disease (PD) and suggests that defects in the protein lead to symptoms by promoting nerve-cell suicide.

Patients with PD lose dopamine-producing neurons; without the neurotransmitter, they suffer uncontrolled movements that worsen with time (see Andersen Review). Scientists aren't sure why the neurons die, but mounting evidence implicates snafus in protein disposal. Most patients accumulate protein clumps in their brain cells. Furthermore, the majority of individuals who suffer from inherited PD harbor mutations in the parkin gene, whose protein product normally helps stamp other proteins with a molecule called ubiquitin, which marks them for destruction. PD-linked parkin mutations disrupt this capability (see "Deadly Giveaway"). By identifying parkin's quarry, researchers might learn how defects in the protein cause PD.

Neuroscientist Asa Abeliovich of Columbia University in New York City and colleagues discovered that parkin clutches two proteins--called hSel-10 and Cul1--that team up with a third protein to form a ubiquitin-adding enzyme called the SCF complex. Initial experiments revealed that parkin, hSel-10, and Cul1 form a trio in the test tube and in human brains.

The identity of parkin's partners suggested a possible target. As part of SCF, hSel-10 selects molecules for ubiquitin tagging. One of these--cyclin E--initiates cell suicide, or apoptosis, and PD patients often accumulate cyclin E in affected brain regions. The researchers postulated that parkin normally ubiquitinates cyclin E, and defective parkin allows cyclin E to accumulate and kill neurons, spurring PD. To test this idea, they determined whether parkin and its cronies flag cyclin E for the scrap heap. In the test tube, the trio stapled ubiquitin to cyclin E. Further studies gauged whether parkin alters cyclin E quantities in brain cells. The team members isolated neurons from mouse embryos and augmented or destroyed parkin. Then they exposed the cells to kainate--a chemical that spurs cyclin E accumulation--and measured survival rates. Neurons with extra parkin held less cyclin E and persisted longer than did cells with diminished amounts of parkin. Scientists had proposed that parkin defects kill neurons because of a general accumulation of garbage, says Abeliovich. But the results suggest that the protein is "specifically involved in the cell death machinery," he says.

Previous strategies sought parkin prey based on their ability to bind to the protein (see "Dumpster Diving"), but the new work suggests that the approach might not reveal the physiologically relevant targets. Researchers should instead look for proteins that are captured by the parkin-containing triumvirate, says neuroscientist Karen O'Malley of Washington University in St. Louis, Missouri. She isn't convinced, however, that the parkin-deficient cells are dying from apoptosis; she'd like to see additional indicators of that process. Nevertheless, "the whole scenario makes a lot of sense," says neuroscientist Mark Mattson of the National Institute on Aging Laboratory of Neurosciences in Baltimore, Maryland. The question, he says, is what makes the dopamine-producing neurons particularly vulnerable to faltering parkin. Familiarity with parkin's social circle might continue to guide researchers in the right direction.

--R. John Davenport

March 12, 2003
  1. J. F. Staropoli et al., Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity. Neuron 37, 735-749 (2003). [Abstract] [Full Text] [CrossRef][Medline]
Citation: R. J. Davenport, Death Be Not Degrading. Sci. SAGE KE 2003, nw41 (12 March 2003);2003/10/nw41

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