epothilone-a and Amyotrophic-Lateral-Sclerosis

Degeneration of the distal neuromuscular circuitry is a hallmark pathology of Amyotrophic Lateral Sclerosis (ALS). The potential for microtubule dysfunction to be a critical pathophysiological mechanism in the destruction of this circuitry is increasingly being appreciated. Stabilization of microtubules to improve neuronal integrity and pathology has been shown to be a particularly favourable approach in other neurodegenerative diseases. We present evidence here that treatment with the microtubule-targeting compound Epothilone D (EpoD) both positively and negatively affects the spinal neuromuscular circuitry in the SOD1. EpoD treatment prevented loss of the spinal motor neuron soma, and distal axon degeneration, early in the disease course. This, however, was not associated with protection of the NMJ synapse and did not improve motor phenotype or clinical progression. EpoD administration was also found to be neurotoxic at later disease stages. This was evidenced by accelerated motor neuron cell body loss, increasing gliosis, and was associated with detrimental outcomes to motor behaviour, clinical assessment and survival.. The results suggest that EpoD accelerates disease progression in the SOD1

Topics: Amyotrophic Lateral Sclerosis; Animals; Axons; Disease Models, Animal; Disease Progression; Epothilones; Hand Strength; Male; Mice; Mice, Transgenic; Motor Neurons; Motor Skills; Neuromuscular Junction; Superoxide Dismutase-1

Topics: Amyotrophic Lateral Sclerosis; Animals; Disease Progression; Epothilones; Mice