Human Molecular Genetics Advance Access published online on June 16, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn171
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Als2 mRNA splicing variants detected in KO mice rescue severe motor dysfunction phenotype in Als2 knock down zebrafish
1 Center for Excellence in Neuromics, CHUM Research Center - Notre Dame Hospital, Montreal, QC, CANADA 2 Research Centre of CHUL (CHUQ), Department of Anatomy and Physiology, Laval University, Quebec, QC, CANADA 3 Department of Pathology and Cell Biology and Groupe de recherche sur le système nerveux central, Université de Montréal, Montréal, QC, Canada 4 Institut de recherches cliniques de Montréal, Montréal, QC, Canada
* Author to whom correspondence should be addressed Professeur Guy Rouleau MD, PhD Director, Ste-Justine Hospital Research Center and The Center for Excellence in Neuromics 1560, rue Sherbrooke est, Y-3633 Montreal, Que., Canada, H2L 4M1 Phone: (514) 345-4740 Phone: (514) 890-8000 x24699 Fax: (514) 345 4698 or (514) 412-7602 Email: guy.rouleau{at}umontreal.ca
Received January 23, 2008; Revised June 2, 2008; Accepted June 6, 2008
Recessive 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 encoded protein, we generated Als2 knock-out mice and zAls2 knock-down zebrafish. The Als2–/- mice lacking exon 2 and part of exon 3 developed mild signs of neurodegeneration compatible with axonal transport deficiency. In contrast, zAls2 knock-down zebrafish 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 zebrafish phenotype. Thus, we speculate that the newly identified Als2 mRNA species prevent the Als2-KO mice from developing severe neurodegenerative disease and might also regulate the severity of the motor neurons phenotype observed in ALS2 patients.
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