6. ABSTRACT Interferon-? (IFN-?) is believed to play a critical role in the immune-mediated CNS disorder multiple sclerosis (MS) and its mouse model experimental autoimmune encephalomyelitis (EAE). We have demonstrated that IFN-? activates a severe endoplasmic reticulum (ER) stress response in myelinating and remyelinating oligodendrocytes that causes oligodendrocyte apoptosis and myelin abnormalities. Nevertheless, the presence of comparable levels of IFN-? in the unperturbed CNS of adult mice induces only modest ER stress, and does not diminish mature oligodendrocyte survival or result in myelin irregularity. In fact we have shown that the stress response activated in adult oligodendrocytes provides protection against subsequent oligodendroglial insults. The ER stress response activates the pancreatic ER kinase (PERK), which phosphorylates the eukaryotic translation initiation factor 2? and specifically maintains client protein homeostasis in the stressed ER. Our studies demonstrate that developing and remyelinating oligodendrocytes from mice that are haploinsufficient for PERK are more sensitive to the presence of IFN-? and that mature oligodendrocytes from these animals are not protected by the cytokine. We have also found that the regulatory protein growth arrest and DNA damage 34 (GADD34), a stress-inducible regulatory subunit of a phosphatase complex that dephosphorylates eIF2?, is selectively upregulated in myelinating oligodendrocytes in mice that ectopically express IFN-? in the CNS. In the studies outlined in this proposal we plan to characterize in further detail the ER stress response in myelinating oligodendrocytes. For these studies we will manipulate PERK (aim 1) as well as GADD34 (aim 2) activity in myelinating cells to gain a better understanding of the hypersensitive of these cells to the ER stress response. In addition, we will explore the molecular mechanism by which IFN-? elicits the ER stress response in oligodendrocytes. Two possibilities, which are not mutually exclusive, will be explored:
in aim 3 we will determine if IFN-?-stimulated expression of antigen presenting (MHC) molecules, which are processed in the ER, contributes to the stress response, and in aim 4 we will determine whether the increased presence of nitric oxide (NO), which is induced by IFN-?, leads to an activation of the ER stress response. Together, these studies should provide the mechanistic insight necessary for the development of strategies toward the manipulation of the ER stress response in oligodendrocytes. Therapeutic approaches focused on the modulation of the ER stress response might prove beneficial in reducing the number of demyelinated lesions and/or enhancing myelin repair in immune-mediated demyelinating disorders. 7. NARRATIVE Multiple sclerosis is an autoimmune disease characterized by CNS inflammation and demyelination, which are associated with oligodendrocyte apoptosis and axonal degeneration. The underlying premise of the studies described in this proposal is that oligodendrocytes, the myelinating cell of the CNS, are particularly sensitive to the inflammatory reaction. Our studies indicate that the inflammatory response results in a disruption of the secretory pathway in oligodendrocytes, which likely display enhanced sensitivity to such disruptions because of their primary role in the generation of the myelin sheath. The studies described in the current proposal are designed to further characterize this potentially important clinical target in immune-mediated demyelinating disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034939-15
Application #
8288842
Study Section
Special Emphasis Panel (ZRG1-MDCN-M (02))
Program Officer
Utz, Ursula
Project Start
1996-12-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
15
Fiscal Year
2012
Total Cost
$330,138
Indirect Cost
$115,763
Name
University of Chicago
Department
Neurology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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Wang, Lijun; Popko, Brian; Roos, Raymond P (2014) An enhanced integrated stress response ameliorates mutant SOD1-induced ALS. Hum Mol Genet 23:2629-38
Hussien, Yassir; Cavener, Douglas R; Popko, Brian (2014) Genetic inactivation of PERK signaling in mouse oligodendrocytes: normal developmental myelination with increased susceptibility to inflammatory demyelination. Glia 62:680-91
Lin, Wensheng; Lin, Yifeng; Li, Jin et al. (2013) Oligodendrocyte-specific activation of PERK signaling protects mice against experimental autoimmune encephalomyelitis. J Neurosci 33:5980-91
Wang, Lijun; Popko, Brian; Roos, Raymond P (2011) The unfolded protein response in familial amyotrophic lateral sclerosis. Hum Mol Genet 20:1008-15
Lin, Wensheng; Lin, Yifeng (2010) Interferon-ýý inhibits central nervous system myelination through both STAT1-dependent and STAT1-independent pathways. J Neurosci Res 88:2569-77
Lin, Wensheng; Popko, Brian (2009) Endoplasmic reticulum stress in disorders of myelinating cells. Nat Neurosci 12:379-85
Lin, Wensheng; Kunkler, Phillip E; Harding, Heather P et al. (2008) Enhanced integrated stress response promotes myelinating oligodendrocyte survival in response to interferon-gamma. Am J Pathol 173:1508-17
Ghashghaei, H T; Weimer, Jill M; Schmid, Ralf S et al. (2007) Reinduction of ErbB2 in astrocytes promotes radial glial progenitor identity in adult cerebral cortex. Genes Dev 21:3258-71
Lin, Wensheng; Bailey, Samantha L; Ho, Hanson et al. (2007) The integrated stress response prevents demyelination by protecting oligodendrocytes against immune-mediated damage. J Clin Invest 117:448-56

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