T 514 890-8000, poste 28832
Amyotrophic lateral sclerosis (ALS) is characterized by the selective loss of motor neurons. Motor neurons are unique in both their metabolic demand and architecture, and both are intricately linked. Efficient transport of cellular cargoes along the axonal process (which can be as much as one meter in length) depends on energy supplied by mitochondria. Furthermore, mitochondria are themselves cargos of axonal transport that must be delivered to the synapse so as to provide the necessary fuel for neurotransmission. Disease pathology includes disturbances in both of these elements, namely disrupted mitochondrial ultrastructure and axonal aggregates in both familial and sporadic ALS cases. Mouse models confirm a defect in the axonal transport of at least one defined cargo, although it remains unknown if broader errors in intracellular trafficking exist. In addition, while various defects in mitochondrial metabolism have been reported, it remains unclear if these defects are unique to motor neurons and how they might participate in disease initiation. To examine how mitochondrial trafficking and axonal transport contribute to disease in vivo, we have generated a new transgenic mouse model in which mitochondria of motor neurons are fluorescently-labeled. These mice, in combination with rodents which develop an ALS-like phenotype, will be examined. Specifically, mitochondrial trafficking, dynamics, and axonal transport will be followed in relation to disease stage using confocal imaging of live motor axons. In addition, since mitochondria from motor neurons are labeled in these animals, motor neuron mitochondria will be isolated and assessed for multiple metabolic parameters. Complementary experiments in motor neuron cultures are also used.
- E. Kabashi*, P.N. Valdmanis*, P. Dion, D. Spiegelman, B.J. McConkey, C. Vande Velde, J.-P. Bouchard, L. Lacomblez, K. Pochigaeva, F. Salachas, P.-F. Pradat, W. Camu, V. Meininger, N. Dupre, and G.A. Rouleau. (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nature Genetics. Epub 2008 Mar 30. * equal contributions
- C. Vande Velde, T.M. Miller, N.R. Cashman, and D.W. Cleveland. (2008). Selective association of misfolded ALS-linked mutant SOD1 with the cytoplasmic face of mitochondria. Proceedings of the National Academy of Sciences (PNAS), 105:4022-4027. Epub 2008 Feb 22.
- S.A. Detmer, C. Vande Velde, D.W. Cleveland, and D.C. Chan. (2008) Hindlimb gait defects due to motor axon loss and reduced distal muscles in a transgenic mouse model of Charcot-Marie-Tooth type 2A. Human Molecular Genetics, 17:367-75. Epub 2007 Oct 24.
- R. Rakhit, J. Robertson, C. Vande Velde, P. Horne, D.M. Ruth, J. Griffin, D.W. Cleveland, N.R. Cashman, and A. Chakrabartty. (2007) An immunological epitope selective for pathologically misfolded SOD1 in ALS. Nature Medicine, 13:754-759. Epub 2007 May 7.
- S. Boillée, C. Vande Velde, and D.W. Cleveland (2006). ALS: A disease of motor neurons and their non-neuronal neighbors. Neuron 52:39-59. (Review)
- C. Vande Velde, M.L. Garcia, X. Yin, B.D. Trapp, and D.W. Cleveland. (2004). The neuroprotective factor Wlds does not attenuate mutant SOD1-mediated motor neuron disease. Neuromolecular Medicine 5:193-204.
- K. Yamanaka*, C. Vande Velde*, E. Eymard-Pierre, E. Bertini, O. Boespflug-Tanguy, and D.W. Cleveland. (2003) Unstable mutants in the peripheral endosomal membrane component ALS2 cause early-onset motor neuron disease. Proceedings of the National Academy of Sciences (PNAS) 100:16041-16046. * equal contributions