. Tau promotes neurodegeneration via DRP1 mislocalization in vivo. Neuron. 2012 Aug 23;75(4):618-32. PubMed.

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  1. A Critical Role of Mitochondrial Dynamics in the Pathogenesis of AD
    Dr. Feany and colleagues should be congratulated for an elegant Drosophila genetic study. They convincingly demonstrated that tau overexpression causes mitochondrial elongation in Drosophila through actin-stabilization mediated DLP1 (aka Drp1) mislocalization. Because mitochondrial fission/fusion deficiency may lead to mitochondria with heterogeneous size, it can be very tricky, or sometimes misleading, to determine whether mitochondrial fission/fusion is impaired in vivo based on measurement of mitochondrial length at a static point only. Ideally, the conclusion should be strengthened by genetic manipulation of mitochondrial dynamics. Drosophila is a very useful tool in this respect. Indeed, on top of the finding that mitochondria become elongated in tau overexpressing Drosophila, DuBoff et al. further demonstrated that Mfn knockdown or DLP1 overexpression rescued tau-induced mitochondrial elongation and toxic effects, which makes the conclusion more convincing.

    Their further genetic manipulations demonstrated that actin stabilization impairs mitochondrial translocation of DLP1, which results in elongation. However, this observation appears contradictory to a prior finding that reported disruption of actin filaments attenuated fission and recruitment of DRP1 to mitochondria (De Vos et al., 2005). The authors proposed a model to try to reconcile the difference: “DRP1 and mitochondria are recruited to F-actin, followed by actin-based translocation, leading to mitochondrial localization of DRP1 and subsequent mitochondrial fission”. Basically this is a two-step model: F-actin recruitment of DLP1 and mitochondria as step one, and actin-based DLP1 translocation to mitochondria as step two. There are questions remaining to be answered regarding both steps. Does tau overexpression increase F-actin-associated DLP1, for example? And does reversing tau-induced actin stabilization also reduce F-actin associated DLP1? As for step two, what is the evidence to support the actin-based DLP1 translocation to mitochondria? And how and why is actin involved in DLP1 translocation?

    There are other unanswered questions as well. Abnormal mitochondrial distribution is observed in AD and AD models (Wang et al., 2008a; Wang et al., 2008b; Wang et al., 2009), what about this fly model? And since tau is a microtubule binding protein, are microtubules or tubulin involved and how can that be answered? Reddy et al. demonstrated an interaction between tau and DLP1 (Manczak and Reddy, 2012), how does that fit into the model?

    The next big question is whether these observations in Drosophila have parallels in mammals. The authors tried to demonstrate that mitochondrial elongation occurs in the brain of Tau transgenic mice by measuring mitochondrial length under the light microscope after immunostaining brain sections with a mitochondrial marker. This is not optimal since individual mitochondrion can hardly be distinguished using light microscopy. Ideally, electron microscopy analysis of mitochondrial ultrastructure and genetic manipulation of mitochondrial dynamics in tau mice will give a more definite answer. Given the ongoing debate over the different effect of PINK1 mutations on mitochondrial morphology in Drosophila study (i.e., PINK1 mutations cause mitochondrial elongation in Drosophila) and mammalian cell study (i.e., PINK1 mutations cause mitochondrial fragmentation in mammalian cells), we should be very cautious when extending any findings in Drosophila to mammalian systems. Another issue that needs to be considered in relation to human tauopathies is that overexpression of caspase cleaved tau or tau hyperphosphorylation (i.e., cardinal features of tauopathies) causes mitochondrial fragmentation in mammalian cells. Therefore, how mitochondria may be affected in tau transgenic mice needs to be more carefully determined.

    Overall, it is clear that mitochondrial dynamics is impaired in AD brain and APP transgenic mouse models (Hirai et al., 2001; Wang et al., 2009; Cho et al., 2009; Du et al., 2010; Calkins et al., 2011; Manczak et al., 2011; Manczak and Reddy, 2012). In vitro studies from multiple groups convincingly demonstrated that APP overexpression or exposure to Abeta causes excessive mitochondrial fission and abnormal mitochondrial distribution, which contributes to mitochondrial dysfunction and synaptic deficits (Barsoum et al., 2006; Wang et al., 2008a; Wang et al., 2008b; Cho et al., 2009; Wang et al., 2009; Du et al., 2010; Calkins et al., 2011; Manczak et al., 2011; Manczak and Reddy, 2012). Mel Feany’s study further demonstrated that abnormal mitochondrial dynamics also mediates tau toxicity, which further strengthens the critical role of mitochondrial dynamics in the pathogenesis of AD.

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