Devic's neuromyelitis optica is an inflammatory demyelinating disorder normally restricted to the optic nerves and spinal cord. Since the identification of a specific autoantibody directed against aquaporin 4, neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody, neuromyelitis optica has been considered an entity distinct from multiple sclerosis. Recent findings indicate that the neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody has a pathogenic role through complementdependent astrocyte toxicity. However, the link with demyelination remains elusive. Autoantibodies can act as receptor agonists/antagonists or alter antigen density in their target cells. We hypothesized that the neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody impairs astrocytic function and secondarily leads to demyelination. Rat astrocytes and oligodendrocytes from primary cultures and rat optic nerves were exposed long-term (24 h) to immunoglobulin G in the absence of complement. Immunoglobulin G was purified from the serum of patients with neuromyelitis optica who were either neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody positive or negative, as well as from healthy controls. Flow cytometry analysis showed a reduction of membrane aquaporin 4 and glutamate transporter type 1 on astrocytes following contact with immunoglobulin G purified from neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody positive serum only. The activity of glutamine synthetase, an astrocyte enzyme converting glutamate into glutamine, decreased in parallel, indicating astrocyte dysfunction. Treatment also reduced oligodendrocytic cell processes and approximately 30% oligodendrocytes died. This deleterious effect was confirmed ex vivo; exposed optic nerves showed reduction of myelin basic protein. Immunoglobulin G from neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody seronegative patients and from healthy controls had no similar effect. Neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody did not directly injure oligodendrocytes cultured without astrocytes. A toxic bystander effect of astrocytes damaged by neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody on oligodendrocytes was identified. Progressive accumulation of glutamate in the culture medium of neuromyelitis opticaimmunoglobulin G/aquaporin 4-antibody-treated glial cells supported the hypothesis of a glutamate-mediated excitotoxic death of oligodendrocytes in our models. Moreover, co-treatment of glial cultures with neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody and D+2-amino-5-phosphonopentanoic acid, a competitive antagonist at the N-methyl-D-aspartate/ glutamate receptor, partially protected oligodendrocytes. Co-immunolabelling of oligodendrocyte markers and neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody showed that astrocytic positive processes were in close contact with oligodendrocytes and myelin in rat optic nerves and spinal cord, but far less so in other parts of the central nervous system. This suggests a bystande...

These authors contributed equally to this work.Keywords: ER stress, autophagy, Parkinson, apoptosis, Drosophila, mouse Endoplasmic reticulum (ER) stress has been implicated in neurodegenerative diseases but its relationship and role in disease progression remain unclear. Using genetic and pharmacological approaches, we showed that mild ER stress ("preconditioning") is neuroprotective in Drosophila and mouse models of Parkinson disease. In addition, we found that the combination of mild ER stress and apoptotic signals triggers an autophagic response both in vivo and in vitro. We showed that when autophagy is impaired, ER-mediated protection is lost. We further demonstrated that autophagy inhibits caspase activation and apoptosis. Based on our findings, we conclude that autophagy is required for the neuroprotection mediated by mild ER stress, and therefore ER preconditioning has potential therapeutic value for the treatment of neurodegenerative diseases.

These findings unveil previously unrecognized roles of PSD on synaptic transmission and LTP in the dorsal, but not in the ventral, hippocampus. The fact that the decrease in protein expression of GluR1 and NR1 was not associated with a change in mRNA expression of these receptors suggests that a sleep-induced modulation of translational mechanisms occurs in dorsal CA1.