Neuroprotective Function of Cellular Prion Protein in a Mouse Model of Amyotrophic Lateral Sclerosis

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 SOD1(G93A) mouse in a crossbreeding strategy to study the function of physiological prion protein (Prp). SOD1(G93A)Prp(-/-) mice exhibited a significantly reduced life span, and an earlier onset and accelerated progression of disease, as compared with SOD1(G93A)Prp+/+ mice. Additionally, during disease progression, SOD1(G93A)Prp-/- mice showed impaired rotarod performance, lower body weight, and reduced muscle strength. Histologically, SoD1(G93A)Prp-/- mice showed reduced numbers of spinal cord motor neurons and extended areas occupied by large vacuoles early in the course of die 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 SOD1(G93A)Prp-/- versus SOD1(G93A) mice. In the course of disease, Bcl-2 decreases, nuclear factor-kappa B 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 SOD1(G93A) amyotrophic lateral sclerosis mouse model by influencing neuronal and/or glial factors involved in antioxidative defense, rather than anti-apoptotic signaling. (Am J Pathol 2010, 176:1409-1420; DOI: 10.2353/ajpath.2010.090355)