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The Journal of Neuroscience, October 11, 2006, 26(41):10614-10619; doi:10.1523/JNEUROSCI.3582-06.2006

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Brief Communications
An Inhibitor of Serine Proteases, Neuroserpin, Acts as a Neuroprotective Agent in a Mouse Model of Neurodegenerative Disease

Yannick Simonin,¹ Yves Charron,² Peter Sonderegger,³ Jean-Dominique Vassalli,² and Ann C. Kato¹

¹Departments of Basic Neurosciences and ²Genetic Medicine and Development, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland, and ³Institute of Biochemistry, University of Zurich, CH-8057 Zurich, Switzerland

Correspondence should be addressed to Ann C. Kato, Department of Basic Neuroscience, Centre Médical Universitaire, 1 rue Michel Servet, 1211 Geneva 4, Switzerland. Email: ann.kato{at}medecine.unige.ch

Various studies suggest that proteolytic activity may be involved in a number of neurodegenerative disorders, including stroke and seizure. In this report, we examined the role of tryptic serine proteases, plasminogen activators (PAs), in the evolution of a neurodegenerative disease. Transgenic mice overexpressing an axonally secreted inhibitor of serine proteases (neuroserpin) were crossed with mice characterized by a "dying-back" motor neuron disease [progressive motor neuronopathy (pmn/pmn)]. Compared with pmn/pmn mice that showed an increase in PA activity, double mutant mice had decreased PA activity in sciatic nerves and spinal cord; their lifespan was increased by 50%, their motor behavior was stabilized, and histological analysis revealed increased numbers of myelinated axons and rescue of motoneuron number and size. This is the first report showing that a class of serine proteases (PAs) may be involved in the pathogenesis of a motor neuron disease and more specifically in axonal degeneration. Inhibiting serine proteases could offer a new strategy for delaying these disorders.

Key words: motoneurons; axon; spinal cord; plasminogen activator; neuroserpin; pmn mice

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Received July 4, 2006; accepted Sept. 7, 2006.

Correspondence should be addressed to Ann C. Kato, Department of Basic Neuroscience, Centre Médical Universitaire, 1 rue Michel Servet, 1211 Geneva 4, Switzerland. Email: ann.kato{at}medecine.unige.ch

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