Blocking GluR2–GAPDH ameliorates experimental autoimmune encephalomyelitis

Abstract

ObjectiveMultiple 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.MethodsExperimental 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.ResultsWe 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.InterpretationThe GluR2 -GAPDH complex represents a novel therapeutic target for the development of medications for MS that work through a different mechanism than existing treatments.

Changes of synapses in experimental autoimmune encephalomyelitis by using Fasudil

“…Consistent with these results, ROCK inhibitor Y‐27632 completely blocked AMPA‐induced moesin phosphorylation, but had no effect on NMDA‐induced moesin phosphorylation, indicating a stabilization of glutamatergic synapse of neurons . Other study also indicates that blocking AMPAR pathway improves neurological function, reduces neuron death, rescues demyelination, increases oligodendrocyte survival, and reduces axonal damage in EAE mice . Further studies are needed to clarify the mechanisms underlying our observations.…”

“…As shown in Figure , Fasudil treatment did not influence NMDAR expression, but obviously suppressed AMPAR expression in spinal cord of Fasudil‐treated mice as compared with control EAE mice ( p < 0.05). NMDAR and AMPAR mediate rapid synaptic transmission, and modulate synaptic plasticity, revealing that down‐regulation of AMPAR might improve neurological function and increase oligodendrocyte survival in EAE mice …”

Disrupting GluA2-GAPDH Interaction Affects Axon and Dendrite Development

“…Interestingly, recent reports have demonstrated that p53 acetylation of lysine residues regulates neurodevelopmental processes 22 23 . As GluA2 subunits are also essential in various aspects of neurodevelopment and we observed the existence of GluA2-GAPDH interaction in cells/neurons without glutamate stimulation and post-mortem spinal cord tissues of healthy human subjects, it is likely that this interaction is crucial under physiological conditions in regulating proper development 19 . Therefore, we investigated the functional consequences of disrupting the GluA2-GAPDH interaction using an interfering peptide on neuronal growth and cortical development.…”

“…To achieve this aim, we specifically injected pregnant mice with 5 nmol/g of GluA2-G-Gpep peptide daily from E8-E19, where neurodevelopment is most prominent. Our previous studies have extensively shown that this peptide significantly disrupts GluA2-GAPDH interaction and produces minimal peptide effect 18 19 20 . Recombinant proteins fused to TAT have been used extensively for efficient delivery of full-length functional proteins into animals in vivo , with great success in crossing the blood-brain barrier and placenta 31 32 .…”

“…In our previous studies, we have identified a novel interaction between GluA2 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and that an enhanced complex formation is associated with neuronal cell death 18 19 20 . GAPDH was shown to interact with p53 which subsequently promoted this cell death pathway via p53 phosphorylation 21 .…”