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The Journal of Neuroscience, August 19, 2009, 29(33):10272-10280; doi:10.1523/JNEUROSCI.1975-09.2009

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Neurobiology of Disease
Mechanisms of Primary Axonal Damage in a Viral Model of Multiple Sclerosis

Jayasri Das Sarma,¹ Lawrence C. Kenyon,² Susan T. Hingley,³ and Kenneth S. Shindler⁴

¹Departments of Neurology and ²Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, ³Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania 19131, and ⁴Scheie Eye Institute and FM Kirby Center for Molecular Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Correspondence should be addressed to Jayasri Das Sarma at her present address: Department of Biological Sciences, Neuroscience Group, Indian Institute of Science Education and Research, Kolkata 700106, India. Email: dassarmaj{at}iiserkol.ac.in

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. Recent studies have demonstrated that significant axonal injury also occurs in MS patients and correlates with neurological dysfunction, but it is not known whether this neuronal damage is a primary disease process, or occurs only secondary to demyelination. In the current studies, neurotropic strains of mouse hepatitis virus (MHV) that induce meningitis, encephalitis, and demyelination in the CNS, an animal model of MS, were used to evaluate mechanisms of axonal injury. The pathogenic properties of genetically engineered isogenic spike protein recombinant demyelinating and nondemyelinating strains of MHV were compared. Studies demonstrate that a demyelinating strain of MHV causes concomitant axonal loss and macrophage-mediated demyelination. The mechanism of axonal loss and demyelination in MHV infection is dependent on successful transport of virus from gray matter to white matter using the MHV host attachment spike glycoprotein. Our data show that axonal loss and demyelination can be independent direct viral cytopathic events, and suggest that similar direct axonal damage may occur in MS. These results have important implications for the design of neuroprotective strategies for CNS demyelinating disease, and our model identifies the spike protein as a therapeutic target to prevent axonal transport of neurotropic viruses.

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Received April 27, 2009; revised July 7, 2009; accepted July 9, 2009.

Correspondence should be addressed to Jayasri Das Sarma at her present address: Department of Biological Sciences, Neuroscience Group, Indian Institute of Science Education and Research, Kolkata 700106, India. Email: dassarmaj{at}iiserkol.ac.in

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