Sigma-1 Receptor in Motoneuron Disease.
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 .
Center for Biological Sciences, University of Southampton, Southampton General Hospital, SO16 6YD, Southampton, UK.
Renzo
R
Mancuso
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@uab.cat.
Xavier
X
Navarro
D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism; D000818:Animals; D006801:Humans; D016472:Motor Neuron Disease / Q000378:metabolism*; D009046:Motor Neurons / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism*; D000097605:Sigma-1 Receptor
D017480:Receptors, sigma; D000097605:Sigma-1 Receptor
Amyotrophic lateral sclerosis; Etiopathology; Motoneuron disease; Motoneurons; Sigma-1 receptor