Sigma-1 receptor is a key genetic modulator in amyotrophic lateral sclerosis

• Published in: Human molecular genetics 2020-03, Vol.29 (4), p.529-540
• Main Authors: Couly, Simon, Khalil, Bilal, Viguier, Véronique, Roussel, Julien, Maurice, Tangui, Liévens, Jean-Charles
• Format: Article
• Language: English
• Subjects: Amyotrophic Lateral Sclerosis; Amyotrophic Lateral Sclerosis - genetics; Animals; Animals, Genetically Modified; Animals, Genetically Modified - genetics; Disease Models, Animal; Drosophila melanogaster; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Endoplasmic Reticulum; Endoplasmic Reticulum - metabolism; Life Sciences; Locomotion; Locomotion - drug effects; Mitochondria; Mitochondria - metabolism; Motor Neurons; Motor Neurons - metabolism; Mutation; Mutation - drug effects; Neurobiology; Neurons and Cognition; Neuroprotective Agents; Neuroprotective Agents - pharmacology; Receptors, sigma; Receptors, sigma - genetics; Receptors, sigma - metabolism; Sigma-1 Receptor
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddz267

Abstract Sigma-1 receptor (S1R) is an endoplasmic reticulum (ER) chaperone that not only regulates mitochondrial respiration but also controls cellular defense against ER and oxidative stress. This makes S1R a potential therapeutic target in amyotrophic lateral sclerosis (ALS). Especially, as a missense mutation E102Q in S1R has been reported in few familial ALS cases. However, the pathogenicity of S1RE102Q and the beneficial impact of S1R in the ALS context remain to be demonstrated in vivo. To address this, we generated transgenic Drosophila that expresses human wild-type S1R or S1RE102Q. Expression of mutant S1R in fly neurons induces abnormal eye morphology and locomotor defects in a dose-dependent manner. This was accompanied by abnormal mitochondrial fragmentation, reduced adenosine triphosphate (ATP) levels and a higher fatigability at the neuromuscular junction during high energy demand. Overexpressing IP3 receptor or glucose transporter mitigates the S1RE102Q-induced eye phenotype, further highlighting the role of calcium and energy metabolism in its toxicity. More importantly, we showed that wild-type S1R rescues locomotor activity and ATP levels of flies expressing the key ALS protein, TDP43. Moreover, overexpressing wild-type S1R enhances resistance of flies to oxidative stress. Therefore, our data provide the first genetic evidence that mutant S1R recapitulates ALS pathology in vivo while increasing S1R confers neuroprotection against TDP43 toxicity.