M.F and D.B. contributed equally to this work.
Genetic inactivation of the p66 isoform of ShcA is neuroprotective in a murine model of multiple sclerosis
Article first published online: 25 JAN 2012
© 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd
European Journal of Neuroscience
Volume 35, Issue 4, pages 562–571, February 2012
How to Cite
Su, K. G., Savino, C., Marracci, G., Chaudhary, P., Yu, X., Morris, B., Galipeau, D., Giorgio, M., Forte, M. and Bourdette, D. (2012), Genetic inactivation of the p66 isoform of ShcA is neuroprotective in a murine model of multiple sclerosis. European Journal of Neuroscience, 35: 562–571. doi: 10.1111/j.1460-9568.2011.07972.x
- Issue published online: 14 FEB 2012
- Article first published online: 25 JAN 2012
- Received 22 July 2011, revised 23 November 2011, accepted 25 November 2011
- multiple sclerosis;
- p66 isoform of ShcA
Although multiple sclerosis (MS) has traditionally been considered to be an inflammatory disease, recent evidence has brought neurodegeneration into the spotlight, suggesting that accumulated damage and loss of axons is critical to disease progression and the associated irreversible disability. Proposed mechanisms of axonal degeneration in MS posit cytosolic and subsequent mitochondrial Ca2+ overload, accumulation of pathologic reactive oxygen species (ROS), and mitochondrial dysfunction leading to cell death. In this context, the role of the p66 isoform of ShcA protein (p66) may be significant. The ShcA isoform is uniquely targeted to the mitochondrial intermembrane space in response to elevated oxidative stress, and serves as a redox enzyme amplifying ROS generation in a positive feedforward loop that eventually mediates cell death by activation of the mitochondrial permeability transition pore. Consequently, we tested the hypothesis that genetic inactivation of p66 would reduce axonal injury in a murine model of MS, experimental autoimmune encephalomyelitis (EAE). As predicted, the p66-knockout (p66-KO) mice developed typical signs of EAE, but had less severe clinical impairment and paralysis than wild-type (WT) mice. Histologic examination of spinal cords and optic nerves showed significant axonal protection in the p66-KO tissue, despite similar levels of inflammation. Furthermore, cultured p66-KO neurons treated with agents implicated in MS neurodegenerative pathways showed greater viability than WT neurons. These results confirm the critical role of ROS-mediated mitochondrial dysfunction in the axonal loss that accompanies EAE, and identify p66 as a new pharmacologic target for MS neuroprotective therapeutics.