Feature: ‘Gatekeeper’ protein protects injured brain

A mouse brain following traumatic brain injury. The penumbra effect can be seen around the primary lesion, top right.

This feature appeared in the September/October 2009 issue of Australian Life Scientist. To subscribe to the magazine, go here.

In the brain, two pluses can sometimes be a minus. The brain needs large amounts of iron, copper and zinc to function normally but, in a crisis, these divalent metal ions flood into neurons, triggering toxic oxidation reactions that can cause cells to die en masse.

Several years ago, Professor Seong-Seng Tan, head of the Brain Development Laboratory of Melbourne’s Howard Florey Institute, went looking for genes that are up-regulated in brain cells in response to stroke, traumatic injury or physiological stress.

Neurologists treating patients who have suffered a stroke, or surgeons dealing with brain injuries after car accidents, are all too familiar with the penumbra effect: a wave of programmed cell death that spreads from the site of the injury or blood clot, killing off healthy neurons.

In the first few days after a stroke or brain injury, the penumbra effect can greatly magnify the effect of the primary injury, leaving patients physically debilitated or with serious cognitive deficits.

Tan says that after traumatic injury or stroke, injured neurons produce the excitatory neurotransmitter glutamate, which over-stimulates healthy neurons, causing them to open membrane ion channels.

Metal ions flood into the cells, reaching toxic concentrations that cause oxidative damage to proteins and DNA. Beyond a certain threshold the damage becomes irreparable triggering cell death by apoptosis.

Iron, copper and zinc ions are also implicated in chronic neurodegenerative diseases. The beta amyloid plaques that clog the brains of Alzheimer’s patients are pinned together by zinc and copper ions, while iron binds alpha-synuclein molecules to form Lewy bodies in the brains of Parkinson’s disease patients.

“At the moment, there’s no effective treatment to prevent apoptosis in brain-injured patients, and clot-busting drugs are the only available treatment for stroke,” says Tan.

The rolling wave of programmed cell death propagated by distress signals from dying cells eventually slows and halts. If it didn’t, even relatively minor brain injuries could be lethal. Reasoning that natural selection would have created a circuit-breaker to constrain the penumbra effect, Tan used microarray technology to screen for changes in gene expression after brain injury in a laboratory mouse model.

Tan’s group identified a protein, Ndfip1 (Nedd4 family-interacting protein), that is sharply up-regulated six to 48 hours after brain injury. They needed to understand how Ndfip1 protected neurons before searching for a drug to increase its expression in the brain without unwanted side-effects.

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