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.