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A mutation in dynein rescues axonal transport defects and extends the life span of ALS mice

Kieran, D; Hafezparast, M; Bohnert, S; Dick, JRT; Martin, J; Schiavo, G; Fisher, EMC; (2005) A mutation in dynein rescues axonal transport defects and extends the life span of ALS mice. J CELL BIOL , 169 (4) 561 - 567. 10.1083/jcb.200501085.

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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 similar to 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.

Type: Article
Title: A mutation in dynein rescues axonal transport defects and extends the life span of ALS mice
DOI: 10.1083/jcb.200501085
Keywords: AMYOTROPHIC-LATERAL-SCLEROSIS, MOTOR-NEURON DISEASE, LINKED SOD1 MUTANTS, SUPEROXIDE-DISMUTASE, RETROGRADE TRANSPORT, MOTONEURON DEGENERATION, PROMOTE SURVIVAL, TETANUS TOXIN, MOUSE MODELS, SPINAL-CORD
UCL classification: UCL > School of Life and Medical Sciences
UCL > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology
UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology > Neurodegenerative Diseases
URI: http://discovery.ucl.ac.uk/id/eprint/179523
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