title: Genetic inactivation of the p66 isoform of ShcA is neuroprotective in a murine model of multiple sclerosis.
abstract: 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.
authors.affiliation: Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.
authors.forename: Kimmy G
authors.initials: KG
authors.lastname: Su
authors.forename: Costanza
authors.initials: C
authors.lastname: Savino
authors.forename: Gail
authors.initials: G
authors.lastname: Marracci
authors.forename: Priya
authors.initials: P
authors.lastname: Chaudhary
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Yu
authors.forename: Brooke
authors.initials: B
authors.lastname: Morris
authors.forename: Danielle
authors.initials: D
authors.lastname: Galipeau
authors.forename: Marco
authors.initials: M
authors.lastname: Giorgio
authors.forename: Michael
authors.initials: M
authors.lastname: Forte
authors.forename: Dennis
authors.initials: D
authors.lastname: Bourdette
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology / Q000648:ultrastructure; D049109:Cell Proliferation; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000172:deficiency; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D005620:Freund's Adjuvant / Q000009:adverse effects; D006023:Glycoproteins / Q000009:adverse effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D017254:Leukemic Infiltration / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D063308:Myelin-Oligodendrocyte Glycoprotein; D009413:Nerve Fibers, Myelinated / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D009900:Optic Nerve / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D010446:Peptide Fragments / Q000009:adverse effects; D055765:Shc Signaling Adaptor Proteins / Q000172:deficiency* / Q000378:metabolism; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; D016207:Cytokines; D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; C000631446:PPIF protein, mouse; D010446:Peptide Fragments; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C445081:myelin oligodendrocyte glycoprotein (35-55); D005620:Freund's Adjuvant; D006861:Hydrogen Peroxide; D021983:Cyclophilins