Differential Screening of Mutated SOD1 Transgenic Mice Reveals Early Up-Regulation of a Fast Axonal Transport Component in Spinal Cord Motor Neurons

• Main Authors: Luc Dupuis, Marc de Tapia, Frédérique René, Bernadette Lutz-Bucher, Jon W. Gordon, Luc Mercken, Laurent Pradier, Jean-Philippe Loeffler
• Format: Article
• Language: English
• Published: Elsevier 2000-08-01
• Series: Neurobiology of Disease
• Online Access: http://www.sciencedirect.com/science/article/pii/S0969996100902924

In the present study we analyze the molecular mechanisms underlying motor neuron degeneration in familial amyotrophic lateral sclerosis (FALS). For this, we used a transgenic mouse model expressing the Cu/Zn superoxide dismutase (SOD1) gene with a Gly86 to Arg (G86R) mutation equivalent to that found in a subset of human FALS. Using an optimized suppression subtractive hybridization method, a cDNA specifically up-regulated during the asymptomatic phase in the lumbar spinal cord of G86R mice was identified by sequence analysis as the KIF3-associated protein (KAP3), a regulator of fast axonal transport. RT-PCR analysis revealed that KAP3 induction was an early event arising long before axonal degeneration. Immunohistochemical studies further revealed that KAP3 protein predominantly accumulates in large motor neurons of the ventral spinal cord. We further demonstrated that KAP3 up-regulation occurs independent of any change in the other components of the kinesin II complex. However, since the ubiquitous KIF1A motor is up-regulated, our results show an early and complex rearrangement of the fast axonal transport machinery in the course of FALS pathology.