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Published 23 May 2005. doi:10.1083/jcb.200501085
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 169, Number 4, 561-567
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 A mutation in dynein rescues axonal transport defects and extends the life span of ALS mice

Dairin Kieran1, Majid Hafezparast3, Stephanie Bohnert4, James R.T. Dick1, Joanne Martin5, Giampietro Schiavo4, Elizabeth M.C. Fisher2, and Linda Greensmith1

1 Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, London WC1N 3BG, England, UK
2 Department of Neurodegenerative Disease, Institute of Neurology, London WC1N 3BG, England, UK
3 Department of Biochemistry, University of Sussex, Brighton BN1 9QG, England, UK
4 Molecular Neuropathobiology Laboratory, Cancer Research UK, London Research Institute, London WC2A 3PX, England, UK
5 Neuroscience Centre, ICMS, Queen Mary University of London, The Royal London Hospital, London E1 1BB, England, UK

Correspondence to Linda Greensmith: l.greensmith{at}ion.ucl.ac.uk


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 ~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 SOD1G93A mice during embryonic development. Surprisingly, crossing SOD1G93A mice with Loa/+ mice delays disease progression and significantly increases life span in Loa/SOD1G93A 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.

Abbreviations used in this paper: ALS, amyotrophic lateral sclerosis; EDL, extensor digitorum longus; Loa, Legs at odd angles; F.I., fatigue index; PCNA, proliferating cell nuclear antigen; SOD1, superoxide dismutase; TeNT HC, carboxy-terminal fragment of tetanus neurotoxin; WT, wild-type.


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