title: Neurotrophic factors stabilize microtubules and protect against rotenone toxicity on dopaminergic neurons.
abstract: Parkinson disease is characterized by the selective degeneration of dopaminergic (DA) neurons in substantia nigra. Long term epidemiological studies have implicated exposure to agricultural pesticides as a significant risk factor. Systemic administration of rotenone, a widely used pesticide, causes selective degeneration of nigral DA neurons and Parkinson disease-like symptoms in rats. Our previous study has shown that the microtubule depolymerizing activity of rotenone plays a critical role in its selective toxicity on DA neurons. Rotenone toxicity is mimicked by the microtubule-depolymerizing drug colchicine and attenuated by the microtubule-stabilizing agent taxol. Here we show that nerve growth factor (NGF) significantly reduced rotenone toxicity on TH(+) neurons in midbrain neuronal cultures. The protective effect of NGF was completely abolished by inhibiting the microtubule-associated protein kinase kinase (MEK) and partially reversed by blocking phosphatidylinositol 3-kinase. In addition, NGF decreased colchicine toxicity on TH(+) neurons in a manner dependent on MEK but not phosphatidylinositol 3-kinase. The protective effect of NGF against rotenone toxicity was occluded by the microtubule-stabilizing drug taxol. In a MEK-dependent manner, NGF significantly attenuated rotenone- or colchicine-induced microtubule depolymerization and ensuing accumulation of vesicles in the soma and elevation in protein carbonyls. Moreover, other neurotrophic factors such as brain-derived neurotrophic factor and glia cell line-derived neurotrophic factor also reduced rotenone- or colchicine-induced microtubule depolymerization and death of TH(+) through a MEK-dependent mechanism. Thus, our results suggest that neurotrophic factors activate the microtubule-associated protein kinase pathway to stabilize microtubules, and this action significantly attenuates rotenone toxicity on dopaminergic neurons.
authors.affiliation: Department of Physiology and Biophysics, State University of New York, Buffalo, New York 14214, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Jiang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
authors.forename: Jian
authors.initials: J
authors.lastname: Feng
mesh_terms: D000818:Animals; D003078:Colchicine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D008870:Microtubules / Q000737:chemistry* / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone / Q000494:pharmacology*; D016708:Synaptophysin / Q000378:metabolism; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D009414:Nerve Growth Factors; D016708:Synaptophysin; D014475:Uncoupling Agents; D012402:Rotenone; D020932:Nerve Growth Factor; D017239:Paclitaxel; D003078:Colchicine; D004298:Dopamine