title: Dysfunction in endoplasmic reticulum-mitochondria crosstalk underlies SIGMAR1 loss of function mediated motor neuron degeneration.
abstract: Mutations in Sigma 1 receptor (SIGMAR1) have been previously identified in patients with amyotrophic lateral sclerosis and disruption of Sigmar1 in mouse leads to locomotor deficits. However, cellular mechanisms underlying motor phenotypes in human and mouse with disturbed SIGMAR1 function have not been described so far. Here we used a combination of in vivo and in vitro approaches to investigate the role of SIGMAR1 in motor neuron biology. Characterization of Sigmar1(-/-) mice revealed that affected animals display locomotor deficits associated with muscle weakness, axonal degeneration and motor neuron loss. Using primary motor neuron cultures, we observed that pharmacological or genetic inactivation of SIGMAR1 led to motor neuron axonal degeneration followed by cell death. Disruption of SIGMAR1 function in motor neurons disturbed endoplasmic reticulum-mitochondria contacts, affected intracellular calcium signalling and was accompanied by activation of endoplasmic reticulum stress and defects in mitochondrial dynamics and transport. These defects were not observed in cultured sensory neurons, highlighting the exacerbated sensitivity of motor neurons to SIGMAR1 function. Interestingly, the inhibition of mitochondrial fission was sufficient to induce mitochondria axonal transport defects as well as axonal degeneration similar to the changes observed after SIGMAR1 inactivation or loss. Intracellular calcium scavenging and endoplasmic reticulum stress inhibition were able to restore mitochondrial function and consequently prevent motor neuron degeneration. These results uncover the cellular mechanisms underlying motor neuron degeneration mediated by loss of SIGMAR1 function and provide therapeutically relevant insight into motor neuronal diseases.
authors: 1 Department of Medical Genetics, University of Lausanne, CH-1005 Lausanne, Switzerland 2 Neurodegenerative Studies Laboratory, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland Nathalie.BernardMarissal@unil.ch Nathalie.Bernard@epfl.ch azzedine.hamid@yahoo.fr hazzeddine@ukaachen.de Roman.Chrast@unil.ch Roman.Chrast@ki.se.
authors: Nathalie
authors: N
authors: Bernard-Marissal
authors: 1 Department of Medical Genetics, University of Lausanne, CH-1005 Lausanne, Switzerland.
authors: Jean-Jacques
authors: JJ
authors: Médard
authors: 1 Department of Medical Genetics, University of Lausanne, CH-1005 Lausanne, Switzerland 3 Institute of Neuropathology, RWTH Aachen University, 52074 Aachen, Germany Nathalie.BernardMarissal@unil.ch Nathalie.Bernard@epfl.ch azzedine.hamid@yahoo.fr hazzeddine@ukaachen.de Roman.Chrast@unil.ch Roman.Chrast@ki.se.
authors: Hamid
authors: H
authors: Azzedine
authors: 1 Department of Medical Genetics, University of Lausanne, CH-1005 Lausanne, Switzerland 4 Department of Neuroscience and Department of Clinical Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors: Roman
authors: R
authors: Chrast
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D016472:Motor Neuron Disease / Q000235:genetics* / Q000378:metabolism; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020239:Receptor Cross-Talk; D017480:Receptors, sigma / Q000235:genetics*; D000097605:Sigma-1 Receptor
chemical_list: D017480:Receptors, sigma; D000097605:Sigma-1 Receptor
keywords: MAMs loss; Sigma 1 receptor; mitochondrial and endoplasmic reticulum dysfunction; motor neuron degeneration