Sci. Aging Knowl. Environ., 21 September 2005
Vol. 2005, Issue 38, p. nf74
[DOI: 10.1126/sageke.2005.38.nf74]


Two Ways About It

Phosphate-adding proteins send neurons down different roads to death after a stroke

R. John Davenport

The fast lane or the slow lane will eventually get you to the same place. Similarly, neurons can die quickly or slowly after a stroke, and new work reveals two different proteins that control which route a cell takes. The study clarifies the mechanisms that obliterate neurons and suggests a new target for drug designers.

By halting blood flow, a stroke prevents parts of the brain from getting oxygen, which kills neurons. Cells perish in two ways. Close to the blood blockage, they disgorge large quantities of the neurotransmitter glutamate, which overstimulates and kills neighboring neurons. Farther away, neurons die more slowly by activating proteins that prompt cell suicide. Molecules called cyclin-dependent kinases (Cdks), which adorn various proteins with phosphate groups, contribute to neuron death after a stroke, but different Cdks might lie on the different roads to destruction. Rashidian and colleagues investigated which Cdks influence each death pathway.

First, the researchers engineered cultured neurons to produce defective versions of either Cdk4, which prompts cell splitting, or Cdk5, which aids nerve development. They simulated the "fast" death pathway by withholding oxygen from the cells. Seventy percent of neurons with nonfunctional Cdk5 survived, versus 50% of controls or cells with faulty versions of Cdk4. To simulate the "slow" death pathway, the scientists added drugs that shackle the receptor proteins that detect glutamate and then choked off the cells' oxygen supply. Fewer cells died when they carried a nonfunctional version of Cdk4, compared with normal cells or cells without Cdk5.

Next, the team tested whether removing Cdk4 or Cdk5 protects brains from stroke. The researchers injected one side of rats' brains with a virus that carries a gene for the defective version of either Cdk4 or Cdk5. They then cut off blood to the entire brain, a manipulation that causes slow neuron damage. In the brain half that made nonworking Cdk4, more than twice as many neurons endured the stroke, compared with the normal side. That result is consistent with the protein's suspected role in slow death. Neurons in rats with defective Cdk5 weren't protected. Next, the team injected the genetically modified rat brains with a compound that instigates rapid, glutamate-triggered neuron death. Animals with inactive Cdk5 suffered less damage than did controls or animals with nonoperational Cdk4.

Showing that Cdk4 triggers delayed death whereas Cdk5 incites rapid death is novel, says Matthias Endres, a neurologist at Charit´┐Ż University of Medicine in Berlin, Germany. Preventing swift neuron demise is difficult because strokes happen without warning, but doctors might have time to intervene in the slower pathway to reduce brain damage, he says. However, researchers would need to figure out how to get Cdk4-blocking compounds into the brain and keep them from hampering normal cell division that Cdk4 promotes elsewhere in the body. If scientists can surmount those challenges, they might close at least one of stroke's roads to devastation.

September 21, 2005
  1. J. Rashidian et al., Multiple cyclin-dependent kinases signals are critical mediators of ischemia/hypoxic neuronal death in vitro and in vivo. Proc. Natl. Acad. Sci. U.S.A., 15 September 2005 [e-pub ahead of print]. doi:10.1073/pnas.0500099102 [Abstract/Free Full Text]
Citation: R. J. Davenport, Two Ways About It. Sci. Aging Knowl. Environ. 2005 (38), nf74 (2005).

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