Collapsin Response Mediator Protein 4a (CRMP4a) Is Upregulated in Motoneurons of Mutant SOD1 Mice and Can Trigger Motoneuron Axonal Degeneration and Cell Death

• Published in: The Journal of neuroscience Vol. 30; no. 2; pp. 785 - 796
• Main Authors: Duplan, Laure, Bernard, Nathalie, Casseron, Wilfrid, Dudley, Keith, Thouvenot, Eric, Honnorat, Jerome, Rogemond, Veronique, De Bovis, Beatrice, Aebischer, Patrick, Marin, Philippe, Raoul, Cedric, Henderson, Christopher E, Pettmann, Brigitte
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 13-01-2010; Society for Neuroscience
• Subjects: Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - pathology; Amyotrophic Lateral Sclerosis - physiopathology; Animals; Axons - physiology; Cell Death - genetics; Cells, Cultured; Disease Models, Animal; Electroporation - methods; Embryo, Mammalian; Green Fluorescent Proteins - genetics; Humans; Mice; Mice, Mutant Strains; Motor Neurons - metabolism; Motor Neurons - pathology; Nerve Degeneration - etiology; Nerve Degeneration - genetics; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nitric Oxide - pharmacology; Proteomics - methods; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization - methods; Spinal Cord - cytology; Superoxide Dismutase - genetics; Up-Regulation - drug effects; Up-Regulation - genetics; Vesicular Acetylcholine Transport Proteins - metabolism
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.5411-09.2010

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.