Rotenone selectively kills serotonergic neurons through a microtubule-dependent mechanism.
As a major co-morbidity of Parkinson's disease (PD), depression is associated with the loss of serotonergic neurons. Our recent study has shown that midbrain dopaminergic neurons are particularly vulnerable to microtubule-depolymerizing agents including rotenone, an environmental toxin linked to PD. Here we show that rotenone also selectively killed serotonergic neurons in midbrain neuronal cultures. Its selective toxicity was significantly decreased by the microtubule-stabilizing drug taxol and mimicked by microtubule-depolymerizing agents such as colchicine and nocodazole. Microtubule depolymerization induced by rotenone or colchicine caused vesicle accumulation in the soma and killed serotonergic neurons through a mechanism dependent on serotonin metabolism in the cytosol. Blocking serotonin synthesis or degradation, as well as application of antioxidants, significantly reduced the selective toxicity of rotenone or colchicine. Inhibition of vesicular sequestration of serotonin exerted a selective toxicity on serotonergic neurons that was mitigated by blocking serotonin metabolism. Over-expression of parkin, a protein-ubiquitin E3 ligase that strongly binds to microtubules, greatly attenuated the selective toxicity of rotenone or colchicine. The protective effects of parkin were abrogated by its PD-linked mutations. Together, our results suggest that rotenone and parkin affect the survival of serotonergic neurons by impacting on microtubules in opposing manners.
Ren
Yong
Y
Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, New York, USA.
Feng
Jian
J
D000654:Amobarbital / Q000494:pharmacology; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D003078:Colchicine / Q000494:pharmacology; D042967:Electron Transport Complex I / Q000187:drug effects / Q000378:metabolism; D008636:Mesencephalon / Q000166:cytology; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics; D051381:Rats; D012402:Rotenone / Q000633:toxicity*; D012701:Serotonin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology
D012402:Rotenone; D012701:Serotonin; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D042967:Electron Transport Complex I; D000654:Amobarbital; D003078:Colchicine