15 Aug 2002

Neuronal cell death plays a major role in neurodegenerative diseases, although in many cases the underlying reason(s) for the cellular loss is unknown or highly complex. In tomorrow’s Science, researchers from the Burnham Institute, La Jolla, California, report a new pathway that can cause neuronal apoptosis, or programmed cell death-the covalent modification of extracellular matrix metalloproteinases (MMPs).

MMP activity has been implicated in a variety of neurodegenerative conditions, including stroke and Alzheimer’s disease (for a review see Yong, et al.). Stuart Lipton and colleagues now show that these proteases can be activated by nitric oxide (NO). They found that NO triggers the so-called “cysteine switch” in MMPs, a conformational change that breaks the coordination between a conserved cysteine amino acid and an essential zinc ion (Zn2+), thus activating the enzyme.

First author Zezong Gu and coworkers found that MMP-9 is activated in mice after cerebral ischemia and reperfusion, and that this activation is attenuated in animals receiving inhibitors of neuronal nitric oxide synthase (nNOS) or that have had their nNOS gene removed. Furthermore, the authors found that nNOS and MMP-9 activities co-localized in the damaged brains. The authors reasoned that NO may be nitrosylating the metalloproteinase and confirmed this possibility in vitro by covalently modifying MMP-9 using an NO donor. They then showed that the nitrosylated protease induced apoptosis of neurons in cerebrocortical cell cultures.

Nitrosylated compounds are notoriously short-lived, however, suggesting that modified MMP-9 may suffer further oxidation to a more permanent derivative. Sure enough, using mass spectroscopy, the authors found that the “switch” cysteine can be oxidized by NO donors to the sulfonic acid (-SO3) derivative. What’s more, they found such derivatives in rodents that suffered cerebral ischemia and reperfusion, but significantly, only in the damaged side of the brain.

This data, coupled with the fact that MMP-9 deficient rodents suffer much less stroke damage, suggests that MMP inhibitors may prove to be selective and effective weapons in the fight to maintain viable neurons.—Tom Fagan