Collapsin response mediator protein 4a (CRMP4a) is upregulated in motoneurons of mutant SOD1 mice and can trigger motoneuron axonal degeneration and cell death.
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.
Duplan
Laure
L
Inserm-Avenir Team, Mediterranean Institute of Neurobiology, Inmed, 13273 Marseille, France.
Bernard
Nathalie
N
Casseron
Wilfrid
W
Dudley
Keith
K
Thouvenot
Eric
E
Honnorat
Jérôme
J
Rogemond
Véronique
V
De Bovis
Béatrice
B
Aebischer
Patrick
P
Marin
Philippe
P
Raoul
Cédric
C
Henderson
Christopher E
CE
Pettmann
Brigitte
B
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
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