title: Collapsin response mediator protein 4a (CRMP4a) is upregulated in motoneurons of mutant SOD1 mice and can trigger motoneuron axonal degeneration and cell death.
abstract: Embryonic motoneurons from mutant SOD1 (mSOD1) mouse models of amyotrophic lateral sclerosis (ALS), but not wild-type motoneurons, can be triggered to die by exposure to nitric oxide (NO), leading to activation of a motoneuron-specific signaling pathway downstream of the death receptor Fas/CD95. To identify effectors of mSOD1-dependent cell death, we performed a proteomic analysis. Treatment of cultured mSOD1 motoneurons with NO led to a 2.5-fold increase in levels of collapsin response mediator protein 4a (CRMP4a). In vivo, the percentage of mSOD1 lumbar motoneurons expressing CRMP4 in mSOD1 mice increased progressively from presymptomatic to early-onset stages, reaching a maximum of 25%. Forced adeno-associated virus (AAV)-mediated expression of CRMP4a in wild-type motoneurons in vitro triggered a process of axonal degeneration and cell death affecting 60% of motoneurons, whereas silencing of CRMP4a in mSOD1 motoneurons protected them from NO-induced death. In vivo, AAV-mediated overexpression of CRMP4a but not CRMP2 led to the death of 30% of the lumbar motoneurons and an 18% increase in denervation of neuromuscular junctions in the gastrocnemius muscle. Our data identify CRMP4a as a potential early effector in the neurodegenerative process in ALS.
authors.affiliation: Inserm-Avenir Team, Mediterranean Institute of Neurobiology, Inmed, 13273 Marseille, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Duplan
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bernard
authors.forename: Wilfrid
authors.initials: W
authors.lastname: Casseron
authors.forename: Keith
authors.initials: K
authors.lastname: Dudley
authors.forename: Eric
authors.initials: E
authors.lastname: Thouvenot
authors.forename: Jérôme
authors.initials: J
authors.lastname: Honnorat
authors.forename: Véronique
authors.initials: V
authors.lastname: Rogemond
authors.forename: Béatrice
authors.initials: B
authors.lastname: De Bovis
authors.forename: Patrick
authors.initials: P
authors.lastname: Aebischer
authors.forename: Philippe
authors.initials: P
authors.lastname: Marin
authors.forename: Cédric
authors.initials: C
authors.lastname: Raoul
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Henderson
authors.forename: Brigitte
authors.initials: B
authors.lastname: Pettmann
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001369:Axons / Q000502:physiology; D016923:Cell Death / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018274:Electroporation / Q000379:methods; D004622:Embryo, Mammalian; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009410:Nerve Degeneration / Q000209:etiology / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide / Q000494:pharmacology; D040901:Proteomics / Q000379:methods; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods; D013116:Spinal Cord / Q000166:cytology; D013482:Superoxide Dismutase / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism
chemical_list: C526904:Dpysl3 protein, mouse; D009419:Nerve Tissue Proteins; D050494:Vesicular Acetylcholine Transport Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D009569:Nitric Oxide; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase