In a follow-up experiment, the researchers confirmed that the product of MMP-9, MMP-9 protein, is present in ALS-vulnerable motor neurons, but not in ALS-resistant ones. Further, the researchers found that MMP-9 can be detected not just in lumbar 5 neurons, but also in other types of motor neurons affected by ALS. "It was a perfect correlation." said Dr. Henderson. "In other words, having MMP-9 is an absolute predictor that a motor neuron will die if the disease strikes, at least in mice."
Taking a closer look at the groups of vulnerable motor neurons, the researchers found differences in MMP-9 expression at the single-cell level. Fast-fatigable neurons (which are involved in movements like jumping and sprinting and are the first to die in ALS) were found to have the most MMP-9 protein, whereas slow neurons (which control posture and are only partially affected in ALS) had none. "So, MMP-9 is not only labeling the most vulnerable groups of motor neurons, it is labeling the most vulnerable subtypes within those groups, as well," said Dr. Spiller.
In another experiment, the researchers tested whether MMP-9 has a functional role in ALS by crossing MMP-9 knockout mice with SOD1 mutant mice (a standard mouse model of ALS). Progeny from this cross with no MMP-9 exhibited an 80-day delay in loss of fast-fatigable motor neuron function and a 25 percent longer lifespan, compared with littermates with two copies of the MMP-9 gene. "This effect on nerve-muscle synapses is the largest ever seen in a mouse model of ALS," said Dr. Spiller.
The same effect on motor neuron function was seen when MMP-9 was inactivated in SOD1 mutant mice using chemical injections or virally mediated gene therapy.
"Even after treatment, these mice didn't have a normal lifespan, so i
|Contact: Karin Eskenazi|
Columbia University Medical Center