title: A mutation in dynein rescues axonal transport defects and extends the life span of ALS mice.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterized by motoneuron degeneration and muscle paralysis. Although the precise pathogenesis of ALS remains unclear, mutations in Cu/Zn superoxide dismutase (SOD1) account for approximately 20-25% of familial ALS cases, and transgenic mice overexpressing human mutant SOD1 develop an ALS-like phenotype. Evidence suggests that defects in axonal transport play an important role in neurodegeneration. In Legs at odd angles (Loa) mice, mutations in the motor protein dynein are associated with axonal transport defects and motoneuron degeneration. Here, we show that retrograde axonal transport defects are already present in motoneurons of SOD1(G93A) mice during embryonic development. Surprisingly, crossing SOD1(G93A) mice with Loa/+ mice delays disease progression and significantly increases life span in Loa/SOD1(G93A) mice. Moreover, there is a complete recovery in axonal transport deficits in motoneurons of these mice, which may be responsible for the amelioration of disease. We propose that impaired axonal transport is a prime cause of neuronal death in neurodegenerative disorders such as ALS.
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, London WC1N 3BG, England, UK.
authors.forename: Dairin
authors.initials: D
authors.lastname: Kieran
authors.forename: Majid
authors.initials: M
authors.lastname: Hafezparast
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bohnert
authors.forename: James R T
authors.initials: JR
authors.lastname: Dick
authors.forename: Joanne
authors.initials: J
authors.lastname: Martin
authors.forename: Giampietro
authors.initials: G
authors.lastname: Schiavo
authors.forename: Elizabeth M C
authors.initials: EM
authors.lastname: Fisher
authors.forename: Linda
authors.initials: L
authors.lastname: Greensmith
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D001370:Axonal Transport / Q000235:genetics*; D001369:Axons / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004398:Dyneins / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D020127:Recovery of Function / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics; D015996:Survival Rate
chemical_list: C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D004398:Dyneins