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Sigma-1 Receptor in Motoneuron Disease

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Sigma Receptors: Their Role in Disease and as Therapeutic Targets

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 964))

Abstract

Amyotrophic Lateral Sclerosis (ALS ) is a neurodegenerative disease affecting spinal cord and brain motoneurons , leading to paralysis and early death. Multiple etiopathogenic mechanisms appear to contribute in the development of ALS , including glutamate excitotoxicity, oxidative stress , protein misfolding, mitochondrial defects, impaired axonal transport, inflammation and glial cell alterations. The Sigma-1 receptor is highly expressed in motoneurons of the spinal cord, particularly enriched in the endoplasmic reticulum (ER) at postsynaptic cisternae of cholinergic C-terminals. Several evidences point to participation of Sigma-1R alterations in motoneuron degeneration. Thus, mutations of the transmembrane domain of the Sigma-1R have been described in familial ALS cases. Interestingly, Sigma-1R KO mice display muscle weakness and motoneuron loss. On the other hand, Sigma-1R agonists promote neuroprotection and neurite elongation through activation of protein kinase C on motoneurons in vitro and in vivo after ventral root avulsion. Remarkably, treatment of SOD1 mice, the most usual animal model of ALS , with Sigma-1R agonists resulted in significantly enhanced motoneuron function and preservation, and increased animal survival. Sigma-1R activation also reduced microglial reactivity and increased the glial expression of neurotrophic factors. Two main interconnected mechanisms seem to underlie the effects of Sigma-1R manipulation on motoneurons: modulation of neuronal excitability and regulation of calcium homeostasis. In addition, Sigma-1R also contributes to regulating protein degradation, and reducing oxidative stress. Therefore, the multi-functional nature of the Sigma-1R represents an attractive target for treating aspects of ALS and other motoneuron diseases .

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Authors and Affiliations

  1. Center for Biological Sciences, University of Southampton, Southampton General Hospital, SO16 6YD, Southampton, UK

    Renzo Mancuso

  2. Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain

    Xavier Navarro

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  1. Departments of Cellular Biology and Anatomy and Ophthalmology and the James and Jean Culver Vision Discovery Institute, Medical College of Georgia at Augusta University, Augusta, Georgia, USA

    Sylvia B. Smith

  2. Cellular Pathobiology Section, Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, Baltimore, Maryland, USA

    Tsung-Ping Su

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Mancuso, R., Navarro, X. (2017). Sigma-1 Receptor in Motoneuron Disease. In: Smith, S., Su, TP. (eds) Sigma Receptors: Their Role in Disease and as Therapeutic Targets. Advances in Experimental Medicine and Biology, vol 964. Springer, Cham. https://doi.org/10.1007/978-3-319-50174-1_16

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