Selective knockdown of mutant SOD1 in Schwann cells ameliorates disease in G85R mutant SOD1 transgenic mice

Neurobiology of Disease

Lawrence Wrabetz¹  Lijun Wang²  Peter Pytel³  Raymond P. Roos⁴  M. Laura Feltri⁴ 

[1] Life Sciences, Buffalo, NY 14203, USA;Department of Neurology, The University of Chicago Medical Center, 5841 S. Maryland Avenue, Chicago, IL 60637, USA;Department of Pathology, The University of Chicago Medical Center, 5841 S. Maryland Avenue, Chicago, IL 60637, USA;;Hunter James Kelly Research Institute, SUNY at Buffalo, School of Medicine and Biomedical Sciences, NYS Center of Excellence in Bioinformatics &

关键词: Amyotrophic lateral sclerosis;    Mutant superoxide dismutase type 1;    Non-cell autonomous degeneration;    Schwann cells;    Transgenic mice;    Motor neuron disease;   

DOI  :  

来源: DOAJ

【 摘 要 】

Mutants of superoxide dismutase type 1 (mtSOD1) that have full dismutase activity (e.g., G37R) as well as none (e.g., G85R) cause familial amyotrophic lateral sclerosis (FALS), indicating that mtSOD1-induced FALS results from a toxicity rather than loss in SOD1 enzymatic activity. Still, it has remained unclear whether mtSOD1 dismutase activity can influence disease. A previous study demonstrated that Cre-mediated knockdown of G37R expression in Schwann cells (SCs) of G37R transgenic mice shortened the late phase of disease and survival. These results suggested that the neuroprotective effect of G37R expressed in SCs was greater than its toxicity, presumably because its dismutase activity counteracted reactive oxygen species (ROS). In order to further investigate this, we knocked down G85R in SCs by crossing G85Rflox mice with myelin-protein-zero (P0):Cre mice, which express Cre recombinase in SCs. Knockdown of G85R in SCs of G85R mice delayed disease onset and extended survival indicating that G85R expression in SCs is neurotoxic. These results demonstrate differences in the effect on disease of dismutase active vs. inactive mtSOD1 suggesting that both a loss as well as gain in function of mtSOD1 influence FALS pathogenesis. The results suggest that mtSOD1-induced FALS treatment may have to be adjusted depending on the cell type targeted and particular mtSOD1 involved.

【 授权许可】

Unknown