Research Roundup updates as of May 2009:
Death of spinal cord neurons in ALS dampens protective mechanism
A vicious cycle of nerve cell damage and loss has been identified as a possible contributor to ALS. Identification of this pathway opens the door to targeting it with therapeutic agents.
|Glutamate carries signals between neurons (nerve cells), and there may be too much of it in ALS.
In the cycle, damage to nerve cells (neurons) in the spinal cord results in the loss of an important protective mechanism, causing more neuron loss.
MDA-supported Yongjie Yang at Johns Hopkins University in Baltimore, with colleagues there and at other institutions, describe experiments in mice that clarify the relationship between loss of neurons and loss of the protective mechanism that clears away glutamate from the vicinity of the neurons. The chemical glutamate, when present in excess, is potentially toxic.
The relationship between these phenomena was previously shown in laboratory studies involving cells but not animals.
Jeffrey Rothstein, director of the MDA/ALS Center at Johns Hopkins University in Baltimore, and an MDA research grantee, coordinated the investigators, and Yongjie Yang at Hopkins received direct MDA support for this project. The investigators published their findings March 26, 2009, in Neuron.
Normally, glutamate, a chemical transmitter of signals between nerve cells, is released by a sending neuron, docks on a receiving neuron, and is then quickly cleared away by glutamate transporter proteins produced by neighboring nervous system cells called “astrocytes.” Loss of one of these glutamate transporters, known as EAAT2, is believed to represent a common mechanism for disease propagation in both familial and nonfamilial ALS.
Yang and colleagues showed that, in mice, when glutamate docks on a receiving neuron, neighboring astrocytes start producing a protein called KBBP, which in turn activates production of a glutamate transporter protein called GLT1. These mouse proteins exist under different names in humans; the researchers say KBBP in mice is identical to the human protein hnRNP K, and GLT1 in mice is called EAAT2 in humans.
When the investigators analyzed the results in mice of spinal cord injury, poisoning by the neurotoxin ricin, and an ALS-causing genetic mutation in the gene for the SOD1 protein, they saw a marked drop in both KBBP production and GLT1 production. They surmised that the damage sustained by the glutamate-transmitting neurons caused a reduction in glutamate signaling, which in turn caused a reduction in glutamate clearance.
They say their studies suggest an unfortunate “feed-forward” mechanism, in which loss of glutamate clearance may be the final blow in the demise of neurons affected by various types of insults, including ALS.
Back to top
Perrin named head of ALS TDI
On May 1, the ALS Therapy Development Institute announced that Steve Perrin, the Institute’s chief scientific officer, would also assume the role of chief executive officer. Maureen Lister was appointed president at the same time.
The ALS TDI and MDA, through its Augie’s Quest initiative, are collaborating on a three-year, $36 million drug-discovery effort in ALS.
Perrin succeeds Sean Scott, who died of ALS this February. Perrin, who has a doctorate in biochemistry, came to the ALS TDI in 2007 from the Cambridge, Mass., biotechnology company Biogen Idec, where he was a principal scientist from 2000 to 2007.
Since he came to ALS TDI, Perrin has added new capabilities to the ALS drug-development pipeline and has assembled a research team of 30 full-time professionals to carry out dozens of projects.
Maureen Lister, a corporate operations and finance expert with experience in the biomedical and energy industries, joined ALS TDI in 2007 as chief financial officer. In 2008, she became chief operating officer and will continue to retain both titles, as well as additional responsibilities as president of the Institute.
Back to top