Important neuronal toxicity of microtubule-bound Tau in vivo in Drosophila

Talmat-Amar, Yasmina; Arribat, Yoan; Redt-Clouet, Christelle; Feuillette, Sébastien; Bougé, Anne-Laure; Lecourtois, Magalie; Parmentier, Marie‐Laure

doi:10.1093/hmg/ddr290

Cited by 33 publications

(52 citation statements)

References 36 publications

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“…Indeed, intracellular hypophosphorylated tau was reported to induce apoptosis when it was overexpressed in non-neuronal cells60. Hypophosphorylated tau was also shown to be toxic in Drosophila61. In this model, the toxicity of hypophosphorylated tau was correlated to the impairment of axonal transport.…”

Section: Discussionmentioning

confidence: 96%

Starvation and inhibition of lysosomal function increased tau secretion by primary cortical neurons

Mohamed

Plouffe

Rémillard-Labrosse

et al. 2014

Sci Rep

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Recent studies have demonstrated that human tau can be secreted by neurons and non-neuronal cells, an event linked to the propagation of tau pathology in the brain. In the present study, we confirmed that under physiological conditions, one tau-positive band was detected in the culture medium with an anti-tau antibody recognizing total tau and the Tau-1 antibody directed against unphosphorylated tau. We then examined whether tau secretion was modified upon insults. Tau secretion was increased by starvation [Earle's Balanced Salt Solution (EBSS)], inhibition of lysosomal function (leupeptin) and when both of these conditions were superimposed, this combined treatment having the most important effects on tau secretion. Interestingly, the pattern of tau secretion was distinct from that of control neurons when neurons were treated either with EBSS alone or EBSS + leupeptin. In these conditions, three tau-positive bands were detected in the culture medium. Two of these three bands were immunoreactive to Tau-1 antibody revealing that at least two tau species were released upon these treatments. Collectively, our results indicate that insults such as nutrient deprivation and lysosomal dysfunction observed in neurodegenerative diseases could result in an increase of tau secretion and propagation of tau pathology in the brain.

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Section: Discussionmentioning

confidence: 96%

Starvation and inhibition of lysosomal function increased tau secretion by primary cortical neurons

Mohamed

Plouffe

Rémillard-Labrosse

et al. 2014

Sci Rep

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“…Our axonal transport study focused on vesicular transport of GFP-tagged neuropeptide Y (NPY-GFP) within the Drosophila larval motoneurons, using an OK6 -Gal4 driver [34] [35]. Neuropeptide-Y is a fast axonal transport cargo that is diffusely distributed in wild-type nerves, but accumulates when transport is compromised; forming vesicle clogs along the axons.…”

Section: Resultsmentioning

confidence: 99%

“…We next investigated in further detail the dynamic vesicle movement along the axons, using a non-invasive in vivo technique to follow the vesicle trajectories, through the cuticle of living larvae [34] [35]. Vesicle motion in motoneuron axons was captured in short movies and was recapitulated in representative kymographs for each genotype (Figure 5A).…”

Section: Resultsmentioning

confidence: 99%

“…Following the protocol of Talmat-Amar et al (2011) [35], we anaesthetized third instar female larvae expressing NPY-GFP in their motor neurons with ether during 2 min. Living larvae were mounted ventral side up on a slide in 1% agarose with a coverslip, and viewed with a fluorescent microscope to track vesicle motion in nerves between segments A2–A3.…”

Section: Methodsmentioning

confidence: 99%

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A Huntingtin Peptide Inhibits PolyQ-Huntingtin Associated Defects

et al. 2013

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BackgroundHuntington’s disease (HD) is caused by the abnormal expansion of the polyglutamine tract in the human Huntingtin protein (polyQ-hHtt). Although this mutation behaves dominantly, huntingtin loss of function also contributes to HD pathogenesis. Indeed, wild-type Huntingtin plays a protective role with respect to polyQ-hHtt induced defects.Methodology/Principal FindingsThe question that we addressed here is what part of the wild-type Huntingtin is responsible for these protective properties. We first screened peptides from the Huntingtin protein in HeLa cells and identified a 23 aa peptide (P42) that inhibits polyQ-hHtt aggregation. P42 is part of the endogenous Huntingtin protein and lies within a region rich in proteolytic sites that plays a critical role in the pathogenesis process. Using a Drosophila model of HD, we tested the protective properties of this peptide on aggregation, as well as on different polyQ-hHtt induced neuronal phenotypes: eye degeneration (an indicator of cell death), impairment of vesicular axonal trafficking, and physiological behaviors such as larval locomotion and adult survival. Together, our results demonstrate high protective properties for P42 in vivo, in whole animals. These data also demonstrate a specific role of P42 on Huntington’s disease model, since it has no effect on other models of polyQ-induced diseases, such as spinocerebellar ataxias.Conclusions/SignificanceAltogether our data show that P42, a 23 aa-long hHtt peptide, plays a protective role with respect to polyQ-hHtt aggregation as well as cellular and behavioral dysfunctions induced by polyQ-hHtt in vivo. Our study also confirms the correlation between polyQ-hHtt aggregation and neuronal defects. Finally, these results strongly suggest a therapeutic potential for P42, specific of Huntington’s disease.

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“…For example, phosphorylation at Ser262 and Ser214 sites greatly weakens the MT binding affinity of tau and causes the release of tau proteins into the cytosol, a factor that is thought to be an early event in tau pathology [73,75,87,125]. As discussed previously, studies in animal models including C. elegans [40], Drosophila [126] and mice [127] indicate that hyperphosphorylation events correlate well with vesicular motion in axons, neurohormone release, synaptic loss, neural activity inhibition and lifespan reduction. Ser to Ala mutations at significant phosphorylation sites such as S262A and S356A can greatly reduce ).…”

Section: Hyperphosphorylation and Tau Toxicitymentioning

confidence: 99%

Behind the curtain of tauopathy: a show of multiple players orchestrating tau toxicity

Huang

Zhou

2015

Cell. Mol. Life Sci.

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tau, a microtubule-associated protein, directly binds with microtubules to dynamically regulate the organization of cellular cytoskeletons, and is especially abundant in neurons of the central nervous system. Under disease conditions such as Pick's disease, progressive supranuclear palsy, frontotemporal dementia, parkinsonism linked to chromosome 17 and Alzheimer's disease, tau proteins can self-assemble to paired helical filaments progressing to neurofibrillary tangles. In these diseases, collectively referred to as "tauopathies", alterations of diverse tau modifications including phosphorylation, metal ion binding, glycosylation, as well as structural changes of tau proteins have all been observed, indicating the complexity and variability of factors in the regulation of tau toxicity. Here, we review our current knowledge and hypotheses from relevant studies on tau toxicity, emphasizing the roles of phosphorylations, metal ions, folding and clearance control underlining tau etiology and their regulations. A summary of clinical efforts and associated findings of drug candidates under development is also presented. It is hoped that a more comprehensive understanding of tau regulation will provide us with a better blueprint of tau networking in neuronal cells and offer hints for the design of more efficient strategies to tackle tau-related diseases in the future.

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Important neuronal toxicity of microtubule-bound Tau in vivo in Drosophila

Cited by 33 publications

References 36 publications

Starvation and inhibition of lysosomal function increased tau secretion by primary cortical neurons

Starvation and inhibition of lysosomal function increased tau secretion by primary cortical neurons

A Huntingtin Peptide Inhibits PolyQ-Huntingtin Associated Defects

Behind the curtain of tauopathy: a show of multiple players orchestrating tau toxicity

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