title: Pathways to motor neuron degeneration in transgenic mouse models.
abstract: Amyotrophic lateral sclerosis (ALS) is an adult-onset neurological disorder characterized by the selective loss of motor neurons. A pathological hallmark of both sporadic and familial ALS is the presence of abnormal accumulations of neurofilament and peripherin proteins in motor neurons. In the past decade, transgenic mouse approaches have been used to address the role of such cytoskeletal abnormalities in motor neuron disease and also to unravel the pathogenesis caused by mutations in the gene coding for superoxide dismutase 1 (SOD1) that account for ~20% of familial ALS cases. In mouse models, disparate effects could result from different types of intermediate filament (IF) aggregates. Perikaryal IF accumulations induced by the overexpression of any of the three wild-type neurofilament proteins were quite well tolerated by motor neurons. Indeed, perikaryal swellings provoked by NF-H overexpression can even confer protection against toxicity of mutant SOD1. Other types of IF aggregates seem neurotoxic, such as those found in transgenic mice overexpressing either peripherin or an assembly-disrupting NF-L mutant. Moreover, understanding the toxicity of SOD1 mutations has been surprisingly difficult. The analysis of transgenic mice expressing mutant SOD1 has yielded complex results, suggesting that multiple pathways may contribute to disease that include the involvement of non-neuronal cells.
authors.affiliation: Centre for Research in Neurosciences, McGill University, Research Institute of the McGill University Health Centre, 1650 Cedar Avenue, Montréal, Québec, Canada H3G 1A4.
authors.forename: Janice
authors.initials: J
authors.lastname: Robertson
authors.forename: Jasna
authors.initials: J
authors.lastname: Kriz
authors.forename: Minh Dang
authors.initials: MD
authors.lastname: Nguyen
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Julien
mesh_terms: D000328:Adult; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D007381:Intermediate Filament Proteins / Q000032:analysis; D008562:Membrane Glycoproteins; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008959:Models, Neurological; D016472:Motor Neuron Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000032:analysis; D064531:Peripherins; D013482:Superoxide Dismutase / Q000235:genetics
chemical_list: D007381:Intermediate Filament Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C578994:PRPH protein, human; D064531:Peripherins; D013482:Superoxide Dismutase