title: Annonacin, a natural mitochondrial complex I inhibitor, causes tau pathology in cultured neurons.
abstract: A neurodegenerative tauopathy endemic to the Caribbean island of Guadeloupe has been associated with the consumption of anonaceous plants that contain acetogenins, potent lipophilic inhibitors of complex I of the mitochondrial respiratory chain. To test the hypothesis that annonacin, a prototypical acetogenin, contributes to the etiology of the disease, we investigated whether annonacin affects the cellular distribution of the protein tau. In primary cultures of rat striatal neurons treated for 48 h with annonacin, there was a concentration-dependent decrease in ATP levels, a redistribution of tau from the axons to the cell body, and cell death. Annonacin induced the retrograde transport of mitochondria, some of which had tau attached to their outer membrane. Taxol, a drug that displaces tau from microtubules, prevented the somatic redistribution of both mitochondria and tau but not cell death. Antioxidants, which scavenged the reactive oxygen species produced by complex I inhibition, did not affect either the redistribution of tau or cell death. Both were prevented, however, by forced expression of the NDI1 nicotinamide adenine dinucleotide (NADH)-quinone-oxidoreductase of Saccharomyces cerevisiae, which can restore NADH oxidation in complex I-deficient mammalian cells and stimulation of energy production via anaerobic glycolysis. Consistently, other ATP-depleting neurotoxins (1-methyl-4-phenylpyridinium, 3-nitropropionic, and carbonyl cyanide m-chlorophenylhydrazone) reproduced the somatic redistribution of tau, whereas toxins that did not decrease ATP levels did not cause the redistribution of tau. Therefore, the annonacin-induced ATP depletion causes the retrograde transport of mitochondria to the cell soma and induces changes in the intracellular distribution of tau in a way that shares characteristics with some neurodegenerative diseases.
authors.affiliation: Experimental Neurology, Philipps University, D-35033 Marburg, Germany.
authors.forename: Myriam
authors.initials: M
authors.lastname: Escobar-Khondiker
authors.forename: Matthias
authors.initials: M
authors.lastname: Höllerhage
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Muriel
authors.forename: Pierre
authors.initials: P
authors.lastname: Champy
authors.forename: Antoine
authors.initials: A
authors.lastname: Bach
authors.forename: Christel
authors.initials: C
authors.lastname: Depienne
authors.forename: Gesine
authors.initials: G
authors.lastname: Respondek
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Yamada
authors.forename: Annie
authors.initials: A
authors.lastname: Lannuzel
authors.forename: Takao
authors.initials: T
authors.lastname: Yagi
authors.forename: Etienne C
authors.initials: EC
authors.lastname: Hirsch
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Oertel
authors.forename: Ralf
authors.initials: R
authors.lastname: Jacob
authors.forename: Patrick P
authors.initials: PP
authors.lastname: Michel
authors.forename: Merle
authors.initials: M
authors.lastname: Ruberg
authors.forename: Günter U
authors.initials: GU
authors.lastname: Höglinger
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000166:cytology; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005663:Furans / Q000494:pharmacology*; D007783:Lactones / Q000494:pharmacology*; D016253:Microscopy, Immunoelectron / Q000379:methods; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D017239:Paclitaxel / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D005663:Furans; D007783:Lactones; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D017382:Reactive Oxygen Species; D050257:Tubulin Modulators; D016875:tau Proteins; C053442:annonacin; D000255:Adenosine Triphosphate; D017239:Paclitaxel