Multiple sclerosis (MS) is a demyelinating and degenerative disease of the central nervous system (CNS). The majority of MS patients experience relapsing-remitting symptoms, followed by a secondary progressive phase of disease (24). Immunomodulatory therapies partially alter the disease course of MS during the relapsing-remitting phase; however the secondary progressive phase of the disease remains resistant to such treatments (25). A possible explanation for this dichotomy is that in the secondary phase of disease, the CNS has sustained irreversible damage to both myelin and axons, which can no longer be corrected by compensatory mechanisms. Several studies have recently shown that axonal damage is present in both MS and its animal model experimental autoimmune encephalomyelitis (EAE) and may contribute to fixed neurological deficits (26, 27). Thus, strategies that ameliorate axon damage may prevent chronic disability in MS. The Wlds mouse is a spontaneously occurring mutant with the unique phenotype of protection against several forms of axonal injury. The mechanisms of neuroprotection in this model is currently unknown, however likely relates to the function of the Ube4b/Nmnat chimeric gene (28). We have found that WId mice have an attenuated course of EAE, and have less axonal damage and demyelination than wild-type mice. In addition, we have found that these mice have increased expression of CD200 in the CNS during EAE, correlating with decreased accumulation of macrophages/microglia in the CNS. CD200 is known to be expressed on neurons, and ligation of its receptor CD200R is inhibitory for macrophage/microglial activation. Increased expression of CD200 in the CNS may promote neuroprotection in EAE and potentially in MS. In this revised grant application, our goals are 2 fold. Firstly, we will explore the role of CD200 in attenuating the immune response and neuropathology in the CNS. Macrophages/microglia have been implicated as the primary mediators of axonal damage and demyelination. Strategies to down-regulate their activation, particularly in the CNS may prevent chronic disability. Activation of CD200R by CD200 is 1 such strategy. In this Aim, we will study in more detail the dynamics and distribution of CD200 expression in the CNS in naive Wlds and wild-type mice, as well as during EAE. We will explore the effects of CD200R ligation on microglia and macrophage activation in vitro, and on a model of microglia-induced neurotoxicity. And lastly we will study the effects of CD200 CD200R pathway activation during the effector (chronic) as well as priming stages of EAE. Our second goal focuses on understanding the relationship of the Wlds chimeric gene and substrates such as CD200. Based on our recent preliminary results, which demonstrate decreased ubiquitination of CD200 in Wld spinal cord, we hypothesize that the Wld gene exerts its effects by altering the ubiquitin proteasome pathway (UPS) degradation of certain substrates, leading to the neuroprotective phenotype. Alterations in the UPS are responsible for several neurodegenerative diseases/models. We will explore the relationship between the chimeric protein and CD200. In addition, we will attempt to identify other substrates subject to altered ubiquitination that may play a role in axon protection in the Wlds model. Lastly, we will explore the possibility that inhibition of the UPS may reduce inflammation-mediated axonopathy. We anticipate that results from this final Aim may provide us with the basis for future studies in the role of the UPS pathway in axon-protection in EAE, and potentially in MS.
|Fernandez-Carbonell, Cristina; Vargas-Lowy, David; Musallam, Alexander et al. (2016) Clinical and MRI phenotype of children with MOG antibodies. Mult Scler 22:174-84|
|Imitola, Jaime; Cote, Daniel; Rasmussen, Stine et al. (2011) Multimodal coherent anti-Stokes Raman scattering microscopy reveals microglia-associated myelin and axonal dysfunction in multiple sclerosis-like lesions in mice. J Biomed Opt 16:021109|
|Liu, Yingru; Bando, Yoshio; Vargas-Lowy, David et al. (2010) CD200R1 agonist attenuates mechanisms of chronic disease in a murine model of multiple sclerosis. J Neurosci 30:2025-38|
|Chabas, D; Ness, J; Belman, A et al. (2010) Younger children with MS have a distinct CSF inflammatory profile at disease onset. Neurology 74:399-405|
|Kuntz, Nancy L; Chabas, Dorothee; Weinstock-Guttman, Bianca et al. (2010) Treatment of multiple sclerosis in children and adolescents. Expert Opin Pharmacother 11:505-20|
|Chitnis, Tanuja; Imitola, Jaime; Wang, Yue et al. (2007) Elevated neuronal expression of CD200 protects Wlds mice from inflammation-mediated neurodegeneration. Am J Pathol 170:1695-712|