| Genetic inactivation of the p66 isoform of ShcA is neuroprotective in a murine model of multiple sclerosis. | |
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MedLine Citation:
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PMID: 22277070 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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 Ca(2+) 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. |
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Authors:
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Kimmy G Su; Costanza Savino; Gail Marracci; Priya Chaudhary; Xiaolin Yu; Brooke Morris; Danielle Galipeau; Marco Giorgio; Michael Forte; Dennis Bourdette |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-25 |
Journal Detail:
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Title: The European journal of neuroscience Volume: - ISSN: 1460-9568 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-26 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8918110 Medline TA: Eur J Neurosci Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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© 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd. |
Affiliation:
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Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA Portland VA Medical Center, 3710 SW US Veterans Hospital Rd, Portland, OR 97239, USA European Institute of Oncology, Milan, Italy 20141. |
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