Stabilization of Hyperdynamic Microtubules is Neuroprotective in Amyotrophic Lateral Sclerosis.
From: KineMed, Inc., Emeryville, California 94608, USA. pfanara@kinemed.com
The Journal of biological chemistry
- Publish Date: Aug 2007
- ISSN: 0021-9258
- Volume: 282
- Issue: 32
- Pages: 23465-72
- Medium: Print
- Language: English
- Citation (JAMA): Fanara Patrizia, Banerjee Jayee, Hueck Rommel V, et al. Stabilization of Hyperdynamic Microtubules is Neuroprotective in Amyotrophic Lateral Sclerosis.. J. Biol. Chem. Aug 2007;282:23465-72
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.
Mesh Headings (Keywords): Amyotrophic Lateral Sclerosis, Animals, Axons, Disease Progression, Humans, Kinetics, Mice, Mice, Transgenic, Microtubules, Models, Biological, Neurons, Neuroprotective Agents, Oxygen, Superoxide Dismutase, Water
Check for Full Text / PubMed Unique Identifier (PMID): 17567579
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