부산대학교 도서관

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.yexcr.2006.02.021 Byline: Hanna Wootz (a), Inga Hansson (a), Laura Korhonen (a)(b), Dan Lindholm (a)(b) Keywords: ALS; Transgenic mice; XIAP; Caspase-12; Calpain; Calpastatin; ER stress Abstract: Amyotrophic lateral sclerosis (ALS) is characterized by the selective degeneration of motor neurons. The cause for nerve cell demise is not clear but involves activation of the caspase family of cysteine proteases. We have shown that ER stress and caspase-12 activation occur in ALS transgenic mice carrying the mutant copper/zinc superoxide dismutase (SOD1) gene. In these mice, we found that the antiapoptotic proteins, X-linked Inhibitor of Apoptosis Protein (XIAP) and the related protein, MIAP2 were decreased. To study the role of this, we generated double transgenic mice expressing XIAP in ALS spinal cord neurons using the Thy1 promoter. Overexpression of XIAP inhibited caspase-12 cleavage and reduced calpain activity in the ALS mice. XIAP also reduced the breakdown of calpastatin that is an inhibitor of calpain. In the double transgenic mice, life span was increased by about 12%. These data support the view that XIAP has beneficial effects in ALS and extends survival. The neuroprotective effect of XIAP involves inhibition of caspases and the stabilization of the calpastatin/calpain system that is altered in the ALS mice. Author Affiliation: (a) Department of Neuroscience, Unit of Neurobiology, Uppsala University, Biomedical Centre, Box 587, S-751 23 Uppsala, Sweden (b) Minerva Medical Research Institute, Biomedicum Helsinki, Helsinki, Finland Article History: Received 25 November 2005; Revised 19 February 2006; Accepted 22 February 2006