Tau Promotes Neurodegeneration via DRP1 Mislocalization In Vivo

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Neuron (Impact Factor: 15.05). 08/2012; 75(4):618-32. DOI: 10.1016/j.neuron.2012.06.026
Source: PubMed


Mitochondrial abnormalities have been documented in Alzheimer's disease and related neurodegenerative disorders, but the causal relationship between mitochondrial changes and neurodegeneration, and the specific mechanisms promoting mitochondrial dysfunction, are unclear. Here, we find that expression of human tau results in elongation of mitochondria in both Drosophila and mouse neurons. Elongation is accompanied by mitochondrial dysfunction and cell cycle-mediated cell death, which can be rescued in vivo by genetically restoring the proper balance of mitochondrial fission and fusion. We have previously demonstrated that stabilization of actin by tau is critical for neurotoxicity of the protein. Here, we demonstrate a conserved role for actin and myosin in regulating mitochondrial fission and show that excess actin stabilization inhibits association of the fission protein DRP1 with mitochondria, leading to mitochondrial elongation and subsequent neurotoxicity. Our results thus identify actin-mediated disruption of mitochondrial dynamics as a direct mechanism of tau toxicity in neurons in vivo.

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    • "Spire1C modulates mitochondrial fission via its formin-binding KIND and actin-nucleating WH2-repeat domains Given that actin assembly has been shown to play an important role in regulating mitochondrial fission (De Vos et al., 2005; DuBoff et al., 2012; Korobova et al., 2013, 2014; Hatch et al., 2014; Li et al., 2015), the observation that Spire1C Figure 2. Continued a fluorescence intensity linescan of the rectangular boxed region indicating the inversely related profiles of GFP- ExonC vs mitoRFP. Scale bar: 10 μm. "
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    ABSTRACT: Mitochondrial division, essential for survival in mammals, is enhanced by an inter-organellar process involving ER tubules encircling and constricting mitochondria. The force for constriction is thought to involve actin polymerization by the ER-anchored isoform of the formin protein inverted formin 2 (INF2). Unknown is the mechanism triggering INF2-mediated actin polymerization at ER-mitochondria intersections. We show that a novel isoform of the formin-binding, actin-nucleating protein Spire, Spire1C, localizes to mitochondria and directly links mitochondria to the actin cytoskeleton and the ER. Spire1C binds INF2 and promotes actin assembly on mitochondrial surfaces. Disrupting either Spire1C actin- or formin-binding activities reduces mitochondrial constriction and division. We propose Spire1C cooperates with INF2 to regulate actin assembly at ER-mitochondrial contacts. Simulations support this model's feasibility and demonstrate polymerizing actin filaments can induce mitochondrial constriction. Thus, Spire1C is optimally positioned to serve as a molecular hub that links mitochondria to actin and the ER for regulation of mitochondrial division. DOI:
    eLife Sciences 08/2015; 4. DOI:10.7554/eLife.08828 · 9.32 Impact Factor
    • "The same group also demonstrated that tau modulates mitochondrial dynamics. Pathological tau inhibited the association of the fission protein DRP1 with mitochondria, resulting in mitochondrial elongation (Fig. 4) (DuBoff et al., 2012). In addition, the NAD synthase and chaperone NMNAT was found to interact with tau oligomers and promote their clearance (Fig. 4) (Ali et al., 2012). "
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    ABSTRACT: Alzheimer's disease (AD) is the leading cause of dementia and the most common neurodegenerative disorder. AD is mostly a sporadic disorder and its main risk factor is age, but mutations in three genes that promote the accumulation of the amyloid-β (Aβ42) peptide revealed the critical role of Amyloid precursor protein (APP) processing in AD. Neurofibrillary tangles enriched in tau are the other pathological hallmark of AD, but the lack of causative tau mutations still puzzles researchers. Here, we describe the contribution of a powerful invertebrate model, the fruit fly Drosophila melanogaster, to uncovering the function and pathogenesis of human APP, Aβ42, and tau. APP and tau participate in many complex cellular processes, although their main function is microtubule stabilization and the to-and-fro transport of axonal vesicles. Additionally, expression of secreted Aβ42 induces prominent neuronal death in Drosophila, a critical feature of AD, making this model a popular choice for identifying intrinsic and extrinsic factors mediating Aβ42 neurotoxicity. Overall, Drosophila has made significant contributions to better understand the complex pathology of AD, although additional insight can be expected from combining multiple transgenes, performing genome-wide loss-of-function screens, and testing anti-tau therapies alone or in combination with Aβ42. Copyright © 2015. Published by Elsevier Inc.
    Experimental Neurology 05/2015; 274(Pt A). DOI:10.1016/j.expneurol.2015.05.013 · 4.70 Impact Factor
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    • "Thus, low concentrations of naturally secreted A recapitulate the tau-dependent effects of recombinant A peptides on anterograde axonal transport. Mitochondrial fission and fusion are critical for proper transport and distribution of mitochondria along the axon, and both tau and A have been implicated in fission–fusion imbalance (Wang et al., 2008, 2009; Cho et al., 2009; DuBoff et al., 2012). However, neither hAPP/A expression nor tau reduction altered the length of axonal mitochondria (Fig. S1 C), suggesting that mitochondrial transport deficits in axons of hAPP transgenic neurons are not caused by alterations in mitochondrial fission or fusion. "
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    ABSTRACT: Axonal transport deficits in Alzheimer’s disease (AD) are attributed to amyloid β (Aβ) peptides and pathological forms of the microtubule-associated protein tau. Genetic ablation of tau prevents neuronal overexcitation and axonal transport deficits caused by recombinant Aβ oligomers. Relevance of these findings to naturally secreted Aβ and mechanisms underlying tau’s enabling effect are unknown. Here we demonstrate deficits in anterograde axonal transport of mitochondria in primary neurons from transgenic mice expressing familial AD-linked forms of human amyloid precursor protein. We show that these deficits depend on Aβ1–42 production and are prevented by tau reduction. The copathogenic effect of tau did not depend on its microtubule binding, interactions with Fyn, or potential role in neuronal development. Inhibition of neuronal activity, N-methyl-d-aspartate receptor function, or glycogen synthase kinase 3β (GSK3β) activity or expression also abolished Aβ-induced transport deficits. Tau ablation prevented Aβ-induced GSK3β activation. Thus, tau allows Aβ oligomers to inhibit axonal transport through activation of GSK3β, possibly by facilitating aberrant neuronal activity.
    Journal of Experimental Medicine 05/2015; 212(5):2125OIA25. DOI:10.1084/jem.2125OIA25 · 12.52 Impact Factor
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