Abstract
Mutations in copper/zinc superoxide dismutase 1 (SOD1), a genetic cause of human amyotrophic lateral sclerosis, trigger motoneuron death through unknown toxic mechanisms. We report that transgenic SOD1G93A mice exhibit striking and progressive changes in neuronal microtubule dynamics from an early age, associated with impaired axonal transport. Pharmacologic administration of a microtubule-modulating agent alone or in combination with a neuroprotective drug to symptomatic SOD1G93A mice reduced microtubule turnover, preserved spinal cord neurons, normalized axonal transport kinetics, and delayed the onset of symptoms, while prolonging life by up to 26%. The degree of reduction of microtubule turnover was highly predictive of clinical responses to different treatments. These data are consistent with the hypothesis that hyperdynamic microtubules impair axonal transport and accelerate motor neuron degeneration in amyotrophic lateral sclerosis. Measurement of microtubule dynamics in vivo provides a sensitive biomarker of disease activity and therapeutic response and represents a new pharmacologic target in neurodegenerative disorders.
Highlights
Amyotrophic lateral sclerosis (ALS)2 is a late-onset, progressive neurodegenerative disease affecting motoneurons [1]
Microtubule-based transport is mandatory for survival of motoneurons and muscle cells; changes in slow axonal transport have been linked to neuropathogenesis in mutant superoxide dismutase1 (SOD1) transgenic mice [11,12,13]
In most non-neuronal cells, tubulin dimers and microtubule polymers exist in rapid dynamic equilibrium, as we have recently shown in vivo by isotopic labeling [17]
Summary
Genetic Background of SOD1G93A Mice, Disease Onset, and Survival—All experiments received approval from the local animal use committee and were carried out according to Office of Laboratory Animal Welfare-National Institutes of Health guidelines. The same doses and regimens were chosen for combined treatment with MTMA/riluzole or MTMA/Pio. Drugs were begun in all mice at the symptomatic age of 10 weeks and continued until the end stage (n ϭ 23/group). Statistical Analysis—The fraction of newly synthesized alanine in each sample was calculated as the ratio of the measured EM1 value to the maximal or asymptotic value possible at the measured body water enrichment, calculated by mass isotopomer distribution analysis, as described elsewhere [26]. This ratio represents the fraction of tubulin that was newly synthesized. Software for statistics included SigmaStat 3.0 and Microsoft Excel 2003
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