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Title:
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Glial activation and central synapse loss, but not motoneuron degeneration, are prevented by the sigma-1 receptor agonist PRE-084 in the Smn2B/- mouse model of spinal muscular atrophy
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Author:
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Cerveró Cebrià, Clàudia; Blasco Carmona, Alba; Tarabal Mostazo, Olga; Casanovas i Llorens, Anna; Piedrafita Llorens, Lídia; Navarro, X. (Xavier); Esquerda Colell, Josep; Calderó i Pardo, Jordi
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Notes:
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Spinal muscular atrophy (SMA) is characterized by the loss of α-motoneurons (MNs) with concomitant muscle denervation. MN excitability and vulnerability to disease are particularly regulated by cholinergic synaptic afferents (C-boutons), in which Sigma-1 receptor (Sig1R) is concentrated. Alterations in Sig1R have been associated with MN degeneration. Here, we investigated whether a chronic treatment with the Sig1R agonist PRE-084 was able to exert beneficial effects on SMA. We used a model of intermediate SMA, the Smn2B/− mouse, in which we performed a detailed characterization of the histopathological changes that occur throughout the disease. We report that Smn2B/− mice exhibited qualitative differences in major alterations found in mouse models of severe SMA: Smn2B/− animals showed more prominent MN degeneration, early motor axon alterations, marked changes in sensory neurons, and later MN deafferentation that correlated with conspicuous reactive gliosis and altered neuroinflammatory M1/M2 microglial balance. PRE-084 attenuated reactive gliosis, mitigated M1/M2 imbalance, and prevented MN deafferentation in Smn2B/− mice. These effects were also observed in a severe SMA model, the SMNΔ7 mouse. However, the prevention of gliosis and MN deafferentation promoted by PRE-084 were not accompanied by any improvements in clinical outcome or other major pathological changes found in SMA mice.
This work was supported by grants from the Ministerio de Economía y Competitividad co-financed by FEDER (SAF2015-70801). |
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Subject(s):
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-spinal muscular atrophy
-Motoneuron
-C-boutons
-Microglia
-Sigma-1 receptor
-Motoneuron synaptic afferents
-Smn2B/- mouse
-SMNΔ7 mouse
-Spinal muscular atrophy |
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Rights:
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(c) American Association of Neuropathologists, 2018
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Document type:
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Article
Article - Accepted version |
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Published by:
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American Association of Neuropathologists
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