Major histocompatibility complex class I molecules protect motor neurons from astrocyte-induced toxicity in amyotrophic lateral sclerosis

Astrocytes isolated from individuals with amyotrophic lateral sclerosis (ALS) are toxic to motor neurons (MNs) and play a non–cell autonomous role in disease pathogenesis. The mechanisms underlying the susceptibility of MNs to cell death remain unclear. Here we report that astrocytes derived from either mice bearing mutations in genes associated with ALS or human subjects with ALS reduce the expression of major histocompatibility complex class I (MHCI) molecules on MNs; reduced MHCI expression makes these MNs susceptible to astrocyte-induced cell death. Increasing MHCI expression on MNs increases survival and motor performance in a mouse model of ALS and protects MNs against astrocyte toxicity. Overexpression of a single MHCI molecule, HLA-F, protects human MNs from ALS astrocyte–mediated toxicity, whereas knockdown of its receptor, the killer cell immunoglobulin-like receptor KIR3DL2, on human astrocytes results in enhanced MN death. Thus, our data indicate that, in ALS, loss of MHCI expression on MNs renders them more vulnerable to astrocyte-mediated toxicity

Major Histocompatability Complex Class I Expression and Glial Reaction Influence Spinal Motoneuron Synaptic Plasticity During the Course of Experimental Autoimmune Encephalomyelitis

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Recent studies have shown that major histocompatibility complex class I (MHC I) expression directly influences the stability of nerve terminals. Also, the acute phase of experimental autoimmune encephalomyelitis (EAE) has shown a significant impact on inputs within the spinal cord. Therefore, the present work investigated the synaptic covering of motoneurons during the induction phase of disease and progressive remissions of EAE. EAE was induced in C57BL/6J mice, which were divided into four groups: normal, peak disease, first remission, and second remission. The animals were killed and their lumbar spinal cords processed for in situ hybridization (IH), immunohistochemistry, and transmission electron microscopy (TEM). The results indicated an increase in glial reaction during the peak disease. During this period, the TEM analysis showed a reduction in the synaptic covering of the motoneurons, corresponding to a reduction in synaptophysin immunolabeling and an increase in the MHC I expression. The IH analysis reinforced the immunolabeling results, revealing an increased expression of MHC I mRNA by motoneurons and nonneuronal cells during the peak disease and first remission. The results observed in both remission groups indicated a return of the terminals to make contact with the motoneuron surface. The ratio between excitatory and inhibitory inputs increased, indicating the potential for development of an excitotoxic process. In conclusion, the results presented here indicate that MHC I up-regulation during the course of EAE correlates with the periods of synaptic plasticity induced by the infiltration of autoreactive immune cells and that synaptic plasticity decreases after recurrent peaks of inflammation. J. Comp. Neurol. 518:990-1007, 2010. (C) 2009 Wiley-Liss, Inc.51879901007Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)FAPESP [2006/05055-4, 2007/03645-1, 2009/16879-6]CNPq [304834/2006-8

Glatiramer Acetate Treatment Increases Stability of Spinal Synapses and Down Regulates MHC I during the Course of EAE

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)The recent discovery that the major histocompatibility complex of class I (MHC I) expression has a role in the synaptic elimination process, represented an insight into understanding the cross talk between neurons. In the present study, the possibility that glatiramer acetate (GA) treatment influences the MHC class I expression and the synaptic plasticity process in the spinal cord during the course of EAE was investigated. C57BL/6J mice were induced to EAE and submitted to treatment either with a placebo solution or with GA (0.05mg/animal, subcutaneously, on a daily basis). All the animals were sacrificed at the peak disease (14 days after induction) or at the point of recovery of the clinical signs (21 days after induction). The spinal cords were removed and submitted to immunohistochemical examination, Western blotting and transmission electron microscopy analysis. The results showed that GA treatment was able to decrease synaptic loss during the course of EAE, which correlates with the downregulation of the MHC I complex. The present results reinforce the neuroprotective role of GA treatment, by reducing synaptic loss during the course of the disease. Such action may be associated with the recently described role of MHC I regulation during the synaptic plasticity process.7811881202Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)FAPESP [2011/18991-8