title: Reduced calreticulin levels link endoplasmic reticulum stress and Fas-triggered cell death in motoneurons vulnerable to ALS.
abstract: Cellular responses to protein misfolding are thought to play key roles in triggering neurodegeneration. In the mutant superoxide dismutase (mSOD1) model of amyotrophic lateral sclerosis (ALS), subsets of motoneurons are selectively vulnerable to degeneration. Fast fatigable motoneurons selectively activate an endoplasmic reticulum (ER) stress response that drives their early degeneration while a subset of mSOD1 motoneurons show exacerbated sensitivity to activation of the motoneuron-specific Fas/NO pathway. However, the links between the two mechanisms and the molecular basis of their cellular specificity remained unclear. We show that Fas activation leads, specifically in mSOD1 motoneurons, to reductions in levels of calreticulin (CRT), a calcium-binding ER chaperone. Decreased expression of CRT is both necessary and sufficient to trigger SOD1(G93A) motoneuron death through the Fas/NO pathway. In SOD1(G93A) mice in vivo, reductions in CRT precede muscle denervation and are restricted to vulnerable motor pools. In vitro, both reduced CRT and Fas activation trigger an ER stress response that is restricted to, and required for death of, vulnerable SOD1(G93A) motoneurons. Our data reveal CRT as a critical link between a motoneuron-specific death pathway and the ER stress response and point to a role of CRT levels in modulating motoneuron vulnerability to ALS.
authors.affiliation: INSERM-Avenir Team, The Mediterranean Institute of Neurobiology, 13273 Marseille, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bernard-Marissal
authors.forename: Anice
authors.initials: A
authors.lastname: Moumen
authors.forename: Claire
authors.initials: C
authors.lastname: Sunyach
authors.forename: Christophe
authors.initials: C
authors.lastname: Pellegrino
authors.forename: Keith
authors.initials: K
authors.lastname: Dudley
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Henderson
authors.forename: Cédric
authors.initials: C
authors.lastname: Raoul
authors.forename: Brigitte
authors.initials: B
authors.lastname: Pettmann
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D037282:Calreticulin / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics; D019014:fas Receptor / Q000235:genetics*
chemical_list: D037282:Calreticulin; C491901:FAS protein, human; D019014:fas Receptor; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase