title: An inhibitor of serine proteases, neuroserpin, acts as a neuroprotective agent in a mouse model of neurodegenerative disease.
abstract: 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.
authors.affiliation: Department of Basic Neurosciences, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Simonin
authors.forename: Yves
authors.initials: Y
authors.lastname: Charron
authors.forename: Peter
authors.initials: P
authors.lastname: Sonderegger
authors.forename: Jean-Dominique
authors.initials: JD
authors.lastname: Vassalli
authors.forename: Ann C
authors.initials: AC
authors.lastname: Kato
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D051379:Mice; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000201:enzymology*; D009479:Neuropeptides / Q000096:biosynthesis* / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000627:therapeutic use; D012697:Serine Endopeptidases / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000096:biosynthesis* / Q000627:therapeutic use; D015843:Serpins / Q000096:biosynthesis* / Q000627:therapeutic use; D000097522:Neuroserpin
chemical_list: D009479:Neuropeptides; D018696:Neuroprotective Agents; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors; D015843:Serpins; D000097522:Neuroserpin