Genetic inactivation of the p66 isoform of ShcA is neuroprotective in a murine model of multiple sclerosis

Kimmy G. Su, Costanza Savino, Gail Marracci, Priya Chaudhary, Xiaolin Yu, Brooke Morris, Danielle Galipeau, Marco Giorgio, Michael Forte, Dennis Bourdette

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)562-571
Number of pages10
JournalEuropean Journal of Neuroscience
Volume35
Issue number3-4
DOIs
StatePublished - Feb 2012

Fingerprint

Multiple Sclerosis
Protein Isoforms
Autoimmune Experimental Encephalomyelitis
Reactive Oxygen Species
Cell Death
Neurons
Spinal Nerves
Optic Nerve
Knockout Mice
Paralysis
Oxidation-Reduction
Axons
Disease Progression
Spinal Cord
Oxidative Stress
Inflammation
Wounds and Injuries
Enzymes
Therapeutics

Keywords

  • EAE
  • Mitochondria
  • Multiple sclerosis
  • Neurodegeneration
  • Neuroprotective
  • P66 isoform of ShcA

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Genetic inactivation of the p66 isoform of ShcA is neuroprotective in a murine model of multiple sclerosis. / Su, Kimmy G.; Savino, Costanza; Marracci, Gail; Chaudhary, Priya; Yu, Xiaolin; Morris, Brooke; Galipeau, Danielle; Giorgio, Marco; Forte, Michael; Bourdette, Dennis.

In: European Journal of Neuroscience, Vol. 35, No. 3-4, 02.2012, p. 562-571.

Research output: Contribution to journalArticle

Su, Kimmy G. ; Savino, Costanza ; Marracci, Gail ; Chaudhary, Priya ; Yu, Xiaolin ; Morris, Brooke ; Galipeau, Danielle ; Giorgio, Marco ; Forte, Michael ; Bourdette, Dennis. / Genetic inactivation of the p66 isoform of ShcA is neuroprotective in a murine model of multiple sclerosis. In: European Journal of Neuroscience. 2012 ; Vol. 35, No. 3-4. pp. 562-571.
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