It's always a bonus for researchers when apparently separate pathways for pathogenetic mechanisms in fact conveniently and neatly intertwine. A report by Lipton and colleagues in Science shows how two proposed mechanisms for nerve-cell death are intimately linked, and should therefore help to direct therapies aimed at treating neurological disorders.

It had been known that the nerve-cell damage that triggers their demise during stroke, Alzheimer's disease and other neurodegenerative diseases not only occurs from inside the cell but externally too. The best-characterized nerve-cell-death pathways occur inside cells, but in terms of external mechanisms, two observations had previously been made — levels of matrix metalloproteinases (particularly MMP9) are elevated in neurodegenerative disorders, and nitric oxide (NO) can modulate the activity of proteins (in a manner that can be described as being analogous to phosphorylation) by reacting with cysteine thiols to form an S-nitrosylated derivative.

Now, Lipton and colleagues show that these two events are linked. They found that NO switches on the overexpression of MMP enzymes, which, in turn, chew up the environment that surrounds nerve cells.

Initial in vitro analysis showed that NO can directly activate MMP9 and induce neuronal apoptosis. To confirm their results in vivo, Lipton and colleagues used mass spectrometry to characterize the events during focal ischaemia (the lack of blood supply owing to the occlusion of an artery) and reperfusion (the return of blood to an ischaemic region, which is also accompanied by tissue damage). This showed that MMP9 is activated by S-nitrosylation of a cysteine residue followed by further oxidation to a sulphinic- or sulphonic-acid derivative. This latter step is particularly interesting, as it is irreversible, which would explain the permanent pathophysiological activation of MMP9 that has been observed in cerebral ischaemia and reperfusion.

The authors say that this NO-activated MMP mechanism “confers responsiveness of the extracellular matrix to nitrosative and oxidative stress”, which are found in several conditions, including cerebral ischaemia and neurodegenerative diseases. The extracellular proteolytic cascades that are triggered by MMPs can disrupt the extracellular matrix, contribute to cell detachment and lead to anoikis (apoptosis due to cell detachment from the substrate). So, the authors conclude that preventing NO-activated MMP activity could be a novel way of tackling neurodegenerative diseases.