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

被引:193
作者
Kieran, D
Hafezparast, M
Bohnert, S
Dick, JRT
Martin, J
Schiavo, G
Fisher, EMC
Greensmith, L
机构
[1] Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, London WC1N 3BG, England
[2] Inst Neurol, Dept Neurodegenerat Dis, London WC1N 3BG, England
[3] Univ Sussex, Dept Biochem, Brighton BN1 9QG, E Sussex, England
[4] Canc Res UK, London Res Inst, Mol Neuropathobiol Lab, London WC2A 3PX, England
[5] Queen Mary Univ London, Royal London Hosp, Ctr Neurosci, London E1 1BB, England
基金
英国生物技术与生命科学研究理事会; 英国医学研究理事会;
关键词
D O I
10.1083/jcb.200501085
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:561 / 567
页数:7
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