XIAP decreases caspase-12 cleavage and calpain activity in spinal cord of ALS transgenic mice

详细信息    查看全文

• 作者：Hanna Wootz ; Inga Hansson ; Laura Korhonen and Dan Lindholm
• 关键词：ALS ; Transgenic mice ; XIAP ; Caspase-12 ; Calpain ; Calpastatin ; ER stress
• 刊名：Experimental Cell Research
• 出版年：2006
• 出版时间：10 June 2006
• 年：2006
• 卷：312
• 期：10
• 页码：1890-1898
• 全文大小：592 K

文摘

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.