Abstract
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.
MeSH terms
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology*
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Animals
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Axonal Transport / drug effects
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Blotting, Western
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Dopamine Agents / toxicity
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Dopaminergic Neurons / drug effects*
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Dopaminergic Neurons / metabolism
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Dopaminergic Neurons / pathology
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Epothilones / therapeutic use*
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Immunoenzyme Techniques
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MPTP Poisoning / chemically induced
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MPTP Poisoning / pathology
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MPTP Poisoning / prevention & control*
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Male
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Mice
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Mice, Inbred C57BL
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Microtubules / drug effects*
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Microtubules / metabolism
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Microtubules / pathology
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Nerve Degeneration
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Neurons / drug effects
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Neurons / metabolism
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Neurons / pathology
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Neuroprotective Agents / therapeutic use*
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Parkinsonian Disorders / chemically induced
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Parkinsonian Disorders / pathology
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Parkinsonian Disorders / prevention & control*
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Protein Processing, Post-Translational / drug effects
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Substantia Nigra / drug effects
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Substantia Nigra / metabolism
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Substantia Nigra / pathology
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Tubulin / metabolism
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Tubulin Modulators / therapeutic use
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Tyrosine 3-Monooxygenase / metabolism
Substances
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Dopamine Agents
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Epothilones
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Neuroprotective Agents
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Tubulin
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Tubulin Modulators
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beta3 tubulin, mouse
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
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Tyrosine 3-Monooxygenase
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desoxyepothilone B