title: Microtubule alterations occur early in experimental parkinsonism and the microtubule stabilizer epothilone D is neuroprotective.
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.
authors.affiliation: Department of Biosciences, Università degli Studi di Milano, Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Cartelli
authors.forename: Francesca
authors.initials: F
authors.lastname: Casagrande
authors.forename: Carla Letizia
authors.initials: CL
authors.lastname: Busceti
authors.forename: Domenico
authors.initials: D
authors.lastname: Bucci
authors.forename: Gemma
authors.initials: G
authors.lastname: Molinaro
authors.forename: Anna
authors.initials: A
authors.lastname: Traficante
authors.forename: Daniele
authors.initials: D
authors.lastname: Passarella
authors.forename: Erminio
authors.initials: E
authors.lastname: Giavini
authors.forename: Gianni
authors.initials: G
authors.lastname: Pezzoli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Battaglia
authors.forename: Graziella
authors.initials: G
authors.lastname: Cappelletti
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D001370:Axonal Transport / Q000187:drug effects; D015153:Blotting, Western; D015259:Dopamine Agents / Q000633:toxicity; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D034261:Epothilones / Q000627:therapeutic use*; D007124:Immunoenzyme Techniques; D020267:MPTP Poisoning / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000627:therapeutic use; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D015259:Dopamine Agents; D034261:Epothilones; D018696:Neuroprotective Agents; D014404:Tubulin; D050257:Tubulin Modulators; C462941:beta3 tubulin, mouse; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; C114026:desoxyepothilone B