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NEW COMMON PATHWAY IN NEURODEGENERATIVE DISEASE IS A POSSIBLE DOOR TO A POINT OF NO RETURN

April 8, 2009- A just-out study suggests that what keeps chronic nervous system diseases such as Alzheimer’s, Huntington’s and ALS going — until they overcome the internal protective mechanisms a body can throw at them — may largely come down to poor conversational skills.

In the current issue of the journal Neuron, a team of Johns Hopkins scientists reports uncovering a much-sought molecular path that nerve cells (neurons) use to communicate with their neighboring cells, the astrocytes.

The team also shows how failure of this system could leave the brain and spinal cord vulnerable in disease.

Astrocytes are the most plentiful central nervous system cells. And while scientists have known for some time that they’re critical for neurons’ normal activity and even for their survival, precisely how the two cell types communicate hasn’t been clear.

“This new work shows that neurons dynamically direct astroglia,” says team leader Jeffrey Rothstein, M.D., Ph.D., “but more important to medicine, it defines how neurological disease may spread throughout the nervous system.”

Rothstein directs The Robert Packard Center for ALS Research at Johns Hopkins.

Most exciting, Rothstein says, “is that any number of neurodegenerative diseases appear to hold this downhill process in common, once the disease has started.” And it apparently begins early in disease. “Even when neurons look OK,” says Rothstein, “the conversation between neurons and astrocytes has fallen off.

“Although many other processes go wrong in the diseases, this common mechanism appears key to keeping the disease going, to create further injury,” Rothstein adds.

The focus of the study is on the plentiful neurons that communicate with each other through the neurotransmitter glutamate. While glutamate is a necessary excitatory substance in the nervous system, in excess, it overstimulates and becomes toxic — excitotoxic — to neurons. Fortunately, neighboring astrocytes can mop up the excess via molecular transporters embedded in their outer membranes. The chief transporter is a protein called EAAT2.

Earlier Rothstein’s group showed that astroglia — and their EAAT2 protein — are critical for normal neuron activity. In test rats whose astroglia lack the EAAT2 equivalent there’s not only a flood of toxic glutamate but a resulting neuron death that leads to paralysis.

Post-mortem studies of patients with ALS and animal models of that disease frequently reveal a severe loss of EAAT2.

What the new study shows is that neurons themselves direct the creation of EAAT2 in nearby astrocytes.

Here, the scientists devised a microscopic platform containing two tiny chambers: One held neurons, another astrocytes. In this system, some neurons could send out their long, thin axon processes through microscopic channels that ended in astrocytes. Where axons reached close to astrocytes or touched them — and only there — the astrocytes quickly turned on their genes for the EAAT2 glutamate transporters, the very protein that could protect them from glutamate excess.

A second elegant but more intricate part of the work revealed that as neurons sidle up to astrocytes, they very specifically stimulate a tiny part of the astrocyte gene that turns on EAAT2. This stimulating molecule, called KBBP, highly regulates the right astrocyte genes that ultimately can keep neurons operating.

In the study, astrocytes whose KBBP was high bloomed with transporters. This didn’t occur if neurons in the chamber were poisoned. It also didn’t occur if production of KBBP was blocked.

The researchers next wanted to see if the pathway they’d uncovered was important in real injuries to the spinal cord or brain. They showed, in rodent models, that injuring the spinal cord neurons that control movement, whether by trauma (like spinal cord injury) or poison, plays havoc with nearby astrocytes. When astrocytes lose the connection with neurons, KBBP drops, they don’t make transporters, there’s a flood of glutamate and they themselves begin to sicken.
This accelerates the ongoing injury to neighboring neurons.

And last, animal models of familial ALS proved the principle of neuron-directs-astrocyte-to-mop-up-glutamate. The models carry a gene that causes the disease, and as the neurons deterioriate, the astrocytes follow. “The loss of the glutamate transporter in these animal models follows the path of neuron injury; it spreads through the spinal cord,” says Rothstein.

“Understanding this biology gives us new clues to the ways a neuron’s “neighborhood” forces disease to accelerate,” says Rothstein. “Fortunately, it also gives us ideas for roadblocks to slow the process down.”

This study was supported by The Robert Packard Center for ALS Research, the National Institutes of Health and the Muscular Dystrophy Association.

The research team includes first author Yongjie Yang, Oguz Gozen, Andrew Watkins, Ileana Lorenzini, Angelo Lepore, Yuanzheng Gao, Svetlana Vidensky and Jean Brennan, with the Johns Hopkins School of Medicine, as well as David Poulsen, from the University of Montana, Missoula, Jeong Won Park and Noo Li Jeon with the University of California, Irvine, and Michael B. Robinson, with the University of Pennsylvania.

Media Contact: Christen Brownlee
410-955-7832; cbrownlee@jhmi.edu

 

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