Annonacin, a Natural Complex I Inhibitor of the Mitochondrial Respiratory Chain, causes Tau Pathology in Cultured Neurons.
Unter dem Begriff Tauopathien fasst man eine Gruppe chronisch progredienter neurodegenerativer Erkrankungen zusammen, die durch abnorme Akkumulation von hyperphosphoryliertem Tau Protein im Perykarion neuraler Zellen gekennzeichnet sind. Tau gehört zur Familie der axonalen Mikrotubuli-assoziierten P...
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- Tauopathy is the name given to a group of chronic progressive neurodegenerative disorders that share a common defining denominator, the accumulation of abnormally phosphorylated tau protein in the cytoplasm of neural cells. Tau belongs to the microtubule-associated protein family and is implicated in the stabilisation of microtubules and regulation of axonal transport. A particular tauopathy endemic to the Caribbean island of Guadeloupe has been associated with the consumption of Annonaceae plants that contain annonacin, the most abundant acetogenin, a family of potent lypophilic inhibitors of complex I of the mitochondrial respiratory chain. Previous experimental work has demonstrated the following: 1) Chronic systemic exposure of rats to annonacin induces neuronal cell loss in the brain in a similar pattern to what is observed in the brains of the Guadeloupean patients that have come to autopsy. 2) Annonacin causes concentration-dependent cell death in mesencephalic cultures by depleting cellular energy. To test the hypothesis that annonacin contributes to the aetiology of the human disease, we investigated, in vitro, whether if annonacin affects the phosphorylation state and the cellular distribution of the tau protein and the underlying mechanisms. We found that in primary cultures of rat striatal neurons treated for 48 hours with annonacin, there was concentration-dependent redistribution of tau from the axons to the cell body. The redistributed tau was phosphorylated on several epitopes, as evidenced by phospho-specific antibodies. Complex I inhibition, the molecular mechanism of action of annonacin, has two major primary consequences, 1) an increase in oxidative stress and 2) a decrease in ATP levels. Although radical-scavengers (NAC, Trolox) neutralized the annonacin-induced radical oxygen species, they did not prevent the redistribution of tau. In contrast, stimulation of energy production via anaerobic glycolysis did, suggesting that the somatic redistribution of phosphorylated tau resulted from annonacin-induced energy depletion rather than from oxidative stress. This concept was strengthened by the observation that other energy-depleting neurotoxins (MPP+, 3-NP) also induced somatic accumulation of phosphorylated tau. An electron-microscopic analysis demonstrated there was also a significant accumulation of mitochondria in the cytoplasm of annonacin-intoxicated neurons. About 30% of the phopshorylated tau in the cytoplasm appeared ultrastructurally attached to the outer mitochondrial membrane. Videomicroscopy of living cells demonstrated that annonacin rapidly induced a comprehensive retrograde transport of mitochondria from the neurites to the neuronal soma. We concluded that the annonacin-induced somatic accumulation of tau and mitochondria were functionally linked, since we observed that taxol, a drug that stabilises microtubules and displaces tau, fully blocked the retrograde transport of mitochondria and somatic accumulation of phosphorylated tau. Finally, we found that annonacin led to a depletion of tau protein in axons, which in turn lead to the breakdown of microtubules, as evidenced ultrastructurally. Thus, annonacin appears to induce somatic accumulation of phosphorylated tau by retrograde axonal transport and to impair the axonal integrity. Together, these data suggest that annonacin is capable of inducing changes in the phosphorylation state and intracellular distribution of the microtubule-associated protein tau in a way that has been observed in the human diseases. Therefore, these observations strengthen the hypothesis that regular consumption of Annonaceous plants might be implicated in the aetiology of the Guadeloupean tauopathy.