title: Neuroprotective function of cellular prion protein in a mouse model of amyotrophic lateral sclerosis.
abstract: Transgenic mice expressing human mutated superoxide dismutase 1 (SOD1) linked to familial forms of amyotrophic lateral sclerosis are frequently used as a disease model. We used the SOD1G93A mouse in a cross-breeding strategy to study the function of physiological prion protein (Prp). SOD1G93APrp-/- mice exhibited a significantly reduced life span, and an earlier onset and accelerated progression of disease, as compared with SOD1G93APrp+/+ mice. Additionally, during disease progression, SOD1G93APrp-/- mice showed impaired rotarod performance, lower body weight, and reduced muscle strength. Histologically, SOD1G93APrp-/- mice showed reduced numbers of spinal cord motor neurons and extended areas occupied by large vacuoles early in the course of the disease. Analysis of spinal cord homogenates revealed no differences in SOD1 activity. Using an unbiased proteomic approach, a marked reduction of glial fibrillary acidic protein and enhanced levels of collapsing response mediator protein 2 and creatine kinase were detected in SOD1G93APrp-/- versus SOD1G93A mice. In the course of disease, Bcl-2 decreases, nuclear factor-kappaB increases, and Akt is activated, but these changes were largely unaffected by Prp expression. Exclusively in double-transgenic mice, we detected a significant increase in extracellular signal-regulated kinase 2 activation at clinical onset. We propose that Prp has a beneficial role in the SOD1G93A amyotrophic lateral sclerosis mouse model by influencing neuronal and/or glial factors involved in antioxidative defense, rather than anti-apoptotic signaling.
authors.affiliation: Department of Neurology, University of Ulm, Steinhovelstr.1, 89075 Ulm, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Steinacker
authors.forename: Andreas
authors.initials: A
authors.lastname: Hawlik
authors.forename: Stefan
authors.initials: S
authors.lastname: Lehnert
authors.forename: Olaf
authors.initials: O
authors.lastname: Jahn
authors.forename: Stephen
authors.initials: S
authors.lastname: Meier
authors.forename: Evamaria
authors.initials: E
authors.lastname: Görz
authors.forename: Kerstin E
authors.initials: KE
authors.lastname: Braunstein
authors.forename: Marija
authors.initials: M
authors.lastname: Krzovska
authors.forename: Birgit
authors.initials: B
authors.lastname: Schwalenstöcker
authors.forename: Sarah
authors.initials: S
authors.lastname: Jesse
authors.forename: Christian
authors.initials: C
authors.lastname: Pröpper
authors.forename: Tobias
authors.initials: T
authors.lastname: Böckers
authors.forename: Albert
authors.initials: A
authors.lastname: Ludolph
authors.forename: Markus
authors.initials: M
authors.lastname: Otto
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000473:pathology; D001947:Breeding; D002452:Cell Count; D004247:DNA / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004789:Enzyme Activation; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009046:Motor Neurons / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism*; D000072002:Prion Proteins; D011328:Prions / Q000378:metabolism*; D013116:Spinal Cord / Q000201:enzymology / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D016019:Survival Analysis; D019076:Transgenes / Q000235:genetics; D014617:Vacuoles / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; D018696:Neuroprotective Agents; D000072002:Prion Proteins; D011328:Prions; C512657:Prnp protein, mouse; C000606290:SOD1 protein, human; D004247:DNA; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D019950:Mitogen-Activated Protein Kinase 1