title: Blocking GluR2-GAPDH ameliorates experimental autoimmune encephalomyelitis.
abstract: OBJECTIVE
  Multiple sclerosis (MS) is the most common disabling neurological disease of young adults. The pathophysiological mechanism of MS remains largely unknown and no cure is available. Current clinical treatments for MS modulate the immune system, with the rationale that autoimmunity is at the core of MS pathophysiology.
  
  
  METHODS
  Experimental autoimmune encephalitis (EAE) was induced in mice with MOG35-55 and clinical scoring was performed to monitor signs of paralysis. EAE mice were injected intraperitoneally with TAT-fusion peptides daily from day 10 until day 30 after immunization, and their effects were measured at day 17 or day 30.
  
  
  RESULTS
  We report a novel target for the development of MS therapy, which aimed at blocking glutamate-mediated neurotoxicity through targeting the interaction between the AMPA (2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid) receptor and an interacting protein. We found that protein complex composed of the GluR2 subunit of AMPA receptors and GAPDH (glyceraldehyde-3-phosphate dehydrogenase) was present at significantly higher levels in postmortem tissue from MS patients and in EAE mice, an animal model for MS. Next, we developed a peptide that specifically disrupts the GluR2 -GAPDH complex. This peptide greatly improves neurological function in EAE mice, reduces neuron death, rescues demyelination, increases oligodendrocyte survival, and reduces axonal damage in the spinal cords of EAE mice. More importantly, our peptide has no direct suppressive effect on naive T-cell responses or basal neurotransmission.
  
  
  CONCLUSIONS
  The GluR2 -GAPDH complex represents a novel therapeutic target for the development of medications for MS that work through a different mechanism than existing treatments.
authors.affiliation: Department of Neuroscience, Centre for Addiction and Mental Health Toronto, Ontario, Canada, M5T 1R8.
authors.forename: Dongxu
authors.initials: D
authors.lastname: Zhai
authors.affiliation: Department of Neuroscience, Centre for Addiction and Mental Health Toronto, Ontario, Canada, M5T 1R8.
authors.forename: Frankie H F
authors.initials: FH
authors.lastname: Lee
authors.affiliation: Toronto General Research Institute, University Health Network Toronto, Ontario, Canada.
authors.forename: Cheryl
authors.initials: C
authors.lastname: D'Souza
authors.affiliation: Department of Neuroscience, Centre for Addiction and Mental Health Toronto, Ontario, Canada, M5T 1R8.
authors.forename: Ping
authors.initials: P
authors.lastname: Su
authors.affiliation: Neuroscience & Mental Health, The Hospital for Sick Children Toronto, Ontario, Canada.
authors.forename: Shouping
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Neuroscience & Mental Health, The Hospital for Sick Children Toronto, Ontario, Canada.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Toronto General Research Institute, University Health Network Toronto, Ontario, Canada ; Laboratory Medicine and Pathobiology, University of Toronto Ontario, Canada.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Neuroscience, Centre for Addiction and Mental Health Toronto, Ontario, Canada, M5T 1R8 ; Department of Psychiatry, University of Toronto Ontario, Canada.
authors.forename: Albert H C
authors.initials: AH
authors.lastname: Wong
authors.affiliation: Department of Neuroscience, Centre for Addiction and Mental Health Toronto, Ontario, Canada, M5T 1R8 ; Department of Psychiatry, University of Toronto Ontario, Canada.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu