desoxyepothilone-b and Parkinsonian-Disorders

The role of microtubule (MT) dysfunction in Parkinson's disease is emerging. It is still unknown whether it is a cause or a consequence of neurodegeneration. Our objective was to assess whether alterations of MT stability precede or follow axonal transport impairment and neurite degeneration in experimental parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in C57Bl mice. MPTP induced a time- and dose-dependent increase in fibres with altered mitochondria distribution, and early changes in cytoskeletal proteins and MT stability. Indeed, we observed significant increases in neuron-specific βIII tubulin and enrichment of deTyr tubulin in dopaminergic neurons. Finally, we showed that repeated daily administrations of the MT stabilizer Epothilone D rescued MT defects and attenuated nigrostriatal degeneration induced by MPTP. These data suggest that alteration of ΜΤs is an early event specifically associated with dopaminergic neuron degeneration. Pharmacological stabilization of MTs may be a viable strategy for the management of parkinsonism.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Axonal Transport; Blotting, Western; Dopamine Agents; Dopaminergic Neurons; Epothilones; Immunoenzyme Techniques; Male; Mice; Mice, Inbred C57BL; Microtubules; MPTP Poisoning; Nerve Degeneration; Neurons; Neuroprotective Agents; Parkinsonian Disorders; Protein Processing, Post-Translational; Substantia Nigra; Tubulin; Tubulin Modulators; Tyrosine 3-Monooxygenase