Targeting the Sigma-1 Receptor via Pridopidine Ameliorates Central Features of ALS Pathology in a SOD1 G93A Model

• Published in: Cell death & disease Vol. 10; no. 3; p. 210
• Main Authors: Ionescu, Ariel, Gradus, Tal, Altman, Topaz, Maimon, Roy, Saraf Avraham, Noi, Geva, Michal, Hayden, Michael, Perlson, Eran
• Format: Journal Article
• Language: English
• Published: England 01.03.2019
• Subjects: Amyotrophic Lateral Sclerosis - drug therapy; Amyotrophic Lateral Sclerosis - pathology; Animals; Axonal Transport - drug effects; Axonal Transport - genetics; Cell Death - drug effects; Cell Survival - drug effects; Cell Survival - genetics; Cells, Cultured; Coculture Techniques; Disease Models, Animal; Female; MAP Kinase Signaling System - drug effects; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Transgenic; Motor Neurons - drug effects; Motor Neurons - metabolism; Muscle Cells - drug effects; Muscle Cells - metabolism; Muscle Cells - pathology; Myoblasts, Smooth Muscle; Neuromuscular Junction - drug effects; Neuromuscular Junction - genetics; Neuromuscular Junction - physiology; Piperidines - pharmacology; Piperidines - therapeutic use; Receptors, sigma - genetics; Receptors, sigma - metabolism; Sigma-1 Receptor; Spinal Cord - drug effects; Spinal Cord - metabolism; Spinal Cord - pathology; Superoxide Dismutase-1 - genetics; Superoxide Dismutase-1 - metabolism
• ISSN: 2041-4889

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease affecting both the upper and lower motor neurons (MNs), with no effective treatment currently available. Early pathological events in ALS include perturbations in axonal transport (AT), formation of toxic protein aggregates and Neuromuscular Junction (NMJ) disruption, which all lead to axonal degeneration and motor neuron death. Pridopidine is a small molecule that has been clinically developed for Huntington disease. Here we tested the efficacy of pridopidine for ALS using in vitro and in vivo models. Pridopidine beneficially modulates AT deficits and diminishes NMJ disruption, as well as motor neuron death in SOD1 MNs and in neuromuscular co-cultures. Furthermore, we demonstrate that pridopidine activates the ERK pathway and mediates its beneficial effects through the sigma-1 receptor (S1R). Strikingly, in vivo evaluation of pridopidine in SOD1 mice reveals a profound reduction in mutant SOD1 aggregation in the spinal cord, and attenuation of NMJ disruption, as well as subsequent muscle wasting. Taken together, we demonstrate for the first time that pridopidine improves several cellular and histological hallmark pathologies of ALS through the S1R.