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. Amyotrophic lateral sclerosis (ALS)2 is a late-onset, progressive neurodegenerative disease affecting motoneurons (1). The etiology of the majority of ALS cases is unknown, but ϳ20% of familial disease cases are due to mutations in copper-zinc superoxide dismutase1 (SOD1) (2). This led to the development of SOD1 transgenic mice as models of disease (2-5).Physically, motoneurons are unique, representing the longest cells in the body, with axons of some motoneurons in the spinal cord extending a meter or more to reach an end organ. As a result of this morphology, exceptional demands are placed on motoneurons. Active transport along lengthy axons is required to convey newly made materials from the cell body to the farthest nerve endings, and to convey nutrients and metabolites back to the cell body. Microtubules are an essential component of the neuron's scaffold and represent the "roadway," or conveyer belt, that neurons use to transport nutrients (6 -10). Microtubule-based transport is mandatory for survival of motoneurons and muscle cells; changes in slow axonal transport have been linked to neuropathogenesis in mutant SOD1 transgenic mice (11-13). In addition, the assembly and disassembly of microtubule polymers in motoneurons is highly responsive to cellular insults, such as excitotoxic stimuli (8, 14 -16).The relation between dynamics of microtubules and neuronal pathogenesis has not been explored in detail, in part due to limited techniques for measuring microtubule dynamics in vivo. 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). In neurons, however, this rapid turnover of axonal and dendritic microtubules is believed to be less dynamic due to their interactions with a specific subclass of microtubule-associated proteins (MAPs) (18 -20). This stability of microtubule...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.