2008 Brain Star Award Recipient - François Gros-Louis
Recipient
François Gros-Louis - Biosketch
Postdoctoral fellow
Université Laval
Article
ALS2 mRNA splicing variants detected in KO mice rescue severe motor dysfunction phenotype in ALS2 knock-down zebra fish. Francois Gros-Louis, Jasna Kriz, Edor Kabashi, Jonathan McDearmid, Stephanie Millecamps, Makoto Urushitani, Li Lin, Patrick Dion, Qinzhang Zhu, Pierre Drapeau, Jean-Pierre Julien and Guy Rouleau. Human Molecular Genetics, 2008, Vol 17. Doi: 10.1093/hmg/ddn171
Significance of the paper
ALS2 mutations are linked to three related but slightly different neurodegenerative disorders: amyotrophic lateral sclerosis, hereditary spastic paraplegia and primary lateral sclerosis. To investigate the function of the ALS2, we generated Als2 knock-out mice and zAls2 knock-down zebra fish. The Als2-/- mice developed mild signs of neurodegeneration compatible with axonal transport deficiency. In contrast, zAls2 knock-down zebra fish had severe developmental abnormalities, swimming deficits and motor neuron perturbation. We identified, by RT-PCR, Northern and Western blotting novel Als2 transcripts in mouse central nervous system. These Als2 transcripts were present in Als2 null mice as well as in wild type littermates and some rescued the zebra fish phenotype. Thus, we speculate that the newly identified Als2 mRNA species prevent the Als2-KO mice from developing severe neurodegenerative disease. Our zebra fish model is the first animal model mimicking the severe motor neuron ALS phenotype and may provide a new tool to better understand this yet untreatable disease and indicates, with respect to the ability of both full length Als2 and truncated novel Als2 transcript to rescue motor phenotype in zebra fish, a potential therapeutic benefit of alternate Als2 transcripts. Gene therapy in ALS2-linked diseases may be an important avenue that it is worth exploring. The loss of function approach in zebra fish provided, for the first time, in vivo evidence that zAls2 is not only required for global embryonic development and growth but may also play a specific functional role in cell migration and motor neuron development or maintenance. Furthermore, we also detected in lymphoblastoid cell lines derived from an IAHSP ALS2-linked patient some Als2 transcripts, suggesting a possible role in modifying the ALS phenotype.