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The Journal of Neuroscience, July 18, 2007, 27(29):7827-7837; doi:10.1523/JNEUROSCI.1644-07.2007

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Neurobiology of Disease
Annonacin, a Natural Mitochondrial Complex I Inhibitor, Causes Tau Pathology in Cultured Neurons

Myriam Escobar-Khondiker,^1,2,3 Matthias Höllerhage,¹ Marie-Paule Muriel,^2,3 Pierre Champy,⁴ Antoine Bach,^2,3 Christel Depienne,^2,3 Gesine Respondek,¹ Elizabeth S. Yamada,¹ Annie Lannuzel,^2,3,6 Takao Yagi,⁵ Etienne C. Hirsch,^2,3 Wolfgang H. Oertel,¹ Ralf Jacob,⁷ Patrick P. Michel,^2,3 Merle Ruberg,^2,3 and Günter U. Höglinger¹

¹Experimental Neurology, Philipps University, D-35033 Marburg, Germany, ²INSERM, Unité 679, Experimental Neurology and Therapeutics, 75013 Paris, France, ³Université Pierre et Marie Curie–Paris6, Faculté de Médecine, 75252 Paris, France, ⁴Laboratoire de Pharmacognosie, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8076 BioCIS, Faculté de Pharmacie Paris XI, 92296 Châtenay-Malabry, France, ⁵Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, ⁶Department of Neurology, Centre Hospitalier Universitaire des Antilles et de la Guyane, Pointe-à-Pitre, 97159 Abymes, Guadeloupe, and ⁷Institute of Cytobiology, Philipps University, D-35037 Marburg, Germany

Correspondence should be addressed to Günter U. Höglinger, Experimental Neurology, Philipps University, D-35033 Marburg, Germany. Email: guenter.hoeglinger{at}med.uni-marburg.de

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.

Key words: annonacin; microtubule-associated protein tau; parkinsonism; mitochondrial complex I; NDI1; axonal transport

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Received Dec. 11, 2006; revised June 6, 2007; accepted June 7, 2007.

Correspondence should be addressed to Günter U. Höglinger, Experimental Neurology, Philipps University, D-35033 Marburg, Germany. Email: guenter.hoeglinger{at}med.uni-marburg.de

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