Pharmaceutical integrated stress response enhancement protects oligodendrocytes and provides a potential multiple sclerosis therapeutic

Sharon W. Way, Joseph R. Podojil, Benjamin L. Clayton, Anita Zaremba, Tassie L. Collins, Rejani B. Kunjamma, Andrew P. Robinson, Pedro Brugarolas, Robert H. Miller, Stephen D. Miller and Brian Popko ()
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Sharon W. Way: The University of Chicago Center for Peripheral Neuropathy, The University of Chicago
Joseph R. Podojil: Northwestern University Feinberg School of Medicine
Benjamin L. Clayton: The University of Chicago Center for Peripheral Neuropathy, The University of Chicago
Anita Zaremba: Case Western Reserve University School of Medicine
Tassie L. Collins: Myelin Repair Foundation
Rejani B. Kunjamma: The University of Chicago Center for Peripheral Neuropathy, The University of Chicago
Andrew P. Robinson: Northwestern University Feinberg School of Medicine
Pedro Brugarolas: The University of Chicago Center for Peripheral Neuropathy, The University of Chicago
Robert H. Miller: Case Western Reserve University School of Medicine
Stephen D. Miller: Northwestern University Feinberg School of Medicine
Brian Popko: The University of Chicago Center for Peripheral Neuropathy, The University of Chicago

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: Abstract Oligodendrocyte death contributes to the pathogenesis of the inflammatory demyelinating disease multiple sclerosis (MS). Nevertheless, current MS therapies are mainly immunomodulatory and have demonstrated limited ability to inhibit MS progression. Protection of oligodendrocytes is therefore a desirable strategy for alleviating disease. Here we demonstrate that enhancement of the integrated stress response using the FDA-approved drug guanabenz increases oligodendrocyte survival in culture and prevents hypomyelination in cerebellar explants in the presence of interferon-γ, a pro-inflammatory cytokine implicated in MS pathogenesis. In vivo, guanabenz treatment protects against oligodendrocyte loss caused by CNS-specific expression of interferon-γ. In a mouse model of MS, experimental autoimmune encephalomyelitis, guanabenz alleviates clinical symptoms, which correlates with increased oligodendrocyte survival and diminished CNS CD4+ T cell accumulation. Moreover, guanabenz ameliorates relapse in relapsing-remitting experimental autoimmune encephalomyelitis. Our results provide support for a MS therapy that enhances the integrated stress response to protect oligodendrocytes against the inflammatory CNS environment.

Date: 2015
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DOI: 10.1038/ncomms7532

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