title: Calreticulin levels determine onset of early muscle denervation by fast motoneurons of ALS model mice.
abstract: Although the precise signaling mechanisms underlying the vulnerability of some sub-populations of motoneurons in ALS remain unclear, critical factors such as metallo-proteinase 9 expression, neuronal activity and endoplasmic reticulum stress have been shown to be involved. In the context of SOD1(G93A) ALS mouse model, we previously showed that a two-fold decrease in calreticulin (CRT) is occurring in the vulnerable fast motoneurons. Here, we asked to which extent the decrease in CRT levels was causative to muscle denervation and/or motoneuron degeneration. Toward this goal, a hemizygous deletion of the crt gene in SOD1(G93A) mice was generated since the complete ablation of crt is embryonic lethal. We observed that SOD1(G93A);crt(+/-) mice display increased and earlier muscle weakness and muscle denervation compared to SOD1(G93A) mice. While CRT reduction in motoneurons leads to a strong upregulation of two factors important in motoneuron dysfunction, ER stress and mTOR activation, it does not aggravate motoneuron death. Our results underline a prevalent role for CRT levels in the early phase of muscle denervation and support CRT regulation as a potential therapeutic approach.
authors.affiliation: The Mediterranean Institute of Neurobiology, Inmed, Inserm U901, Marseille, France; The University of Lausanne, Department of Medical Genetics, Lausanne, Switzerland.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bernard-Marissal
authors.affiliation: The Mediterranean Institute of Neurobiology, Inmed, Inserm U901, Marseille, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Sunyach
authors.affiliation: The School of Medicine, Department of Basic Neurosciences, University of Geneva, Geneva, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Marissal
authors.affiliation: The Mediterranean Institute of Neurobiology, Inmed, Inserm U901, Marseille, France; The Neuroscience Institute Montpellier, Inserm UMR1051, Saint Eloi Hospital, Montpellier, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Raoul
authors.affiliation: The Mediterranean Institute of Neurobiology, Inmed, Inserm U901, Marseille, France. Electronic address: brigitte.pettmann@inserm.fr.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Pettmann
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000150:complications* / Q000235:genetics / Q000473:pathology; D000818:Animals; D037282:Calreticulin / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology*; D018908:Muscle Weakness / Q000209:etiology; D009135:Muscular Diseases / Q000209:etiology* / Q000473:pathology; D009410:Nerve Degeneration / Q000209:etiology*; D011950:Receptors, Cholinergic / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics; D058570:TOR Serine-Threonine Kinases; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism
chemical_list: D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D037282:Calreticulin; D015852:Eukaryotic Initiation Factor-2; D011950:Receptors, Cholinergic; C493460:Slc18a3 protein, mouse; D050494:Vesicular Acetylcholine Transport Proteins; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
keywords: ALS; Calreticulin; ER stress; Muscle weakness and denervation; mTOR