by Tom Valeo
Amyotrophic lateral sclerosis (ALS) lays waste to the vast majority of the body’s motor neurons, but preserves a few islands of function, such as eye movement, urination, defecation, and sexual function. Also, slow motor neurons that control posture are far more resistant to the ravages of ALS than the fast-fatigable motor neurons, which initiate quick and forceful muscle contractions.
This discrepancy has enabled researchers at the Columbia University Medical Center to show that a protein known as matrix metalloproteinase-9, or MMP-9, is present in motor neurons susceptible to ALS, but not in those resistant to the disease. This correlation, termed “perfect” by study leader Christopher E. Henderson, PhD, suggests treatments that could slow the inexorable progression of ALS, and perhaps halt it.
“It's an amazing correlation,” said Dr. Henderson, the Gurewitsch and Vidda Foundation professor of rehabilitation and regenerative medicine, professor of pathology and cell biology and neuroscience (in neurology), and co-director of Columbia's Motor Neuron Center, who reported the findings in the Jan. 22 issue of Neuron. “The moment we saw it, I was certain that MMP-9 was at the very least the first marker we had for the vulnerable motor neurons in this model of ALS.”
THE EXPERIMENTAL APPROACH
Working with a mouse model of ALS, the researchers used DNA microarray profiling to compare tens of thousands of genes found in neurons resistant to ALS with genes found in affected neurons. Of the “susceptibility” genes found only in vulnerable motor neurons, the gene for MMP-9 was strongly active into adulthood, when ALS begins. The protein was found in greatest abundance in fast-fatigable neurons, and not found at all in neurons resistant to ALS. This makes the protein “a reliable predictor” of which neurons will die, at least in the mouse model of the disease, according to Dr. Henderson.
The researchers curbed the activity of MMP-9 in the mice by injecting an enzyme inhibitor directly into the central nervous system. “That showed some benefit, but it certainly was not a complete rescue, perhaps because the drug we used is far from perfect,” Dr. Henderson said. “It could also be because MMP-9 may act in two ways to cause neuron degeneration — both by enzymatically digesting specific substrates, and by triggering degeneration pathways by interacting with other proteins. The enzyme inhibitor would only block the first of these. It may be that we need both to inhibit activity and to find ways of reducing levels of MMP-9 protein.”
In another experiment, the researchers crossed MMP-9 knockout mice with the standard mouse model of ALS, which carries a mutant form of superoxide dismutase 1, or SOD1, linked to familial ALS. Progeny with no MMP-9 exhibited an 80-day delay in the loss of fast-fatigable motor neuron function, and lived 25 percent longer than mice carrying two copies of the gene for MMP-9. This benefit is believed to be the largest ever produced in a mouse model of ALS.
“What this says unambiguously, is that reducing the amounts of MMP-9 is a good thing — in the mouse model (of ALS),” Dr. Henderson said. “We need to examine expression in human material much more closely now, and we need to be certain that removing MMP-9 has benefits not only in SOD1 cases, but also in the much more frequent cases of ALS caused by other genes or by sporadic causes.”
For the full discussion of these findings from the study author and outside commentators, see the Mar. 6 issue of Neurology Today. Browse our collection of stories on ALS: http://bit.ly/1gJyVc2.