<i>Drosophila</i> models of human tauopathies indicate that Tau protein toxicity <i>in vivo</i> is mediated by soluble cytosolic phosphorylated forms of the protein

Feuillette, Sébastien; Miguel, Laëtitia; Frébourg, Thierry; Campion, Dominique; Lecourtois, Magalie

doi:10.1111/j.1471-4159.2010.06663.x

Cited by 69 publications

(62 citation statements)

References 31 publications

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“…These results suggest that increased soluble hyperphosphorylated tau causes memory deficits in TMHT mice, supporting the results of other research groups [27,28]. Feuillette et al [29] for example show that accumulation of cytosolic hyperphosphorylated human tau protein correlates with human tau-mediated neurodegeneration in flies. By using a tg mouse with a repressible human tau variant, SantaCruz et al could show that after suppression of the tg tau, memory deficits improved and neuron numbers recovered but NFTs still accumulated [30].…”

Section: Discussionsupporting

confidence: 84%

Elevated Levels of Soluble Total and Hyperphosphorylated Tau Result in Early Behavioral Deficits and Distinct Changes in Brain Pathology in a New Tau Transgenic Mouse Model

Flunkert¹,

Hierzer²,

Löffler³

et al. 2012

Neurodegener Dis

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Tauopathies, characterized by hyperphosphorylation and aggregation of tau protein, include frontotemporal dementias and Alzheimer's disease. To explore disease mechanisms and investigate potential treatments, we generated a transgenic (tg) mouse line overexpressing human tau441 with V337M and R406W mutations. Biochemical characterization of these TMHT (Thy-1 mutated human tau) mice showed a significant increase in human transgene expression relative to endogenous murine tau by Western blot and multi-array immunosorbent assay. Only soluble total tau and phosphorylated tau (ptau at residue Thr¹⁸¹, Ser¹⁹⁹, Thr²³¹ and Thr²³⁵), but not insoluble total tau and ptau were increased. Application of the Phospho-Tau SRM assay revealed that phosphorylation at Ser³⁹⁶ and Ser⁴⁰⁴ in soluble tau in the presence of the R406W mutation was at baseline levels in the cortex of TMHT mice compared to non-tg littermates. Histological analyses showed a progressive increase in human tau protein in the amygdala over age, while hippocampal tau levels remained constant from 2 months onwards. Behavioral testing of TMHT mice in the Morris water maze revealed a distinct progressive spatial learning impairment starting already at 5 months of age. Furthermore, we showed that the TMHT mice have early olfactory deficits. These impairments are unbiased by any motor disturbance or lack of motivation. Our results prove that combination of the V337M and R406W mutations of tau accelerates human tau phosphorylation and induces tau pathology as well as cognitive deficits, making this model a suitable tool for basic research on tau as well as in vivo drug testing.

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Section: Discussionsupporting

confidence: 84%

Elevated Levels of Soluble Total and Hyperphosphorylated Tau Result in Early Behavioral Deficits and Distinct Changes in Brain Pathology in a New Tau Transgenic Mouse Model

Flunkert¹,

Hierzer²,

Löffler³

et al. 2012

Neurodegener Dis

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“…Similarly, bristle loss in the fly notum induced by human WT Tau expression was less pronounced when expression of endogenous dTau was reduced [102]. However, complete removal of dTau did not modify the toxicity associated with expression of human Tau proteins in the eye [120].…”

Section: Fly Taumentioning

confidence: 94%

The Power and Richness of Modelling Tauopathies in Drosophila

Papanikolopoulou

Skoulakis

2011

Mol Neurobiol

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Tauopathies are a group of neurodegenerative disorders characterised by altered levels of phosphorylation or mutations in the neuronal microtubule protein Tau. The heterogeneous pathology of tauopathies suggests differential susceptibility of different neuronal types to wild-type and mutant Tau. The genetic power and facility of the Drosophila model has been instrumental in exploring the molecular aetiologies of tauopathies, identifying additional proteins likely contributing to neuronal dysfunction and toxicity and novel Tau phosphorylations mediating them. Importantly, recent results indicate tissue- and temporal-specific effects on dysfunction and toxicity coupled with differential effects of distinct Tau isoforms within them. Therefore, they reveal an unexpected richness of the Drosophila model that, coupled with its molecular genetic power, will likely play a significant role in our understanding of multiple tauopathies potentially leading to their differential treatment.

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“…Overexpression of tau, for example, inhibits trafficking of vesicles and organelles (119, 120), and tau differentially modulates dynein and kinesin mobility (121). Soluble cytosolic forms of hyperphosphorylated tau appear to be the toxic species (116, 122). Efforts to actively reduce tau in AD would seem to be beneficial.…”

Section: Alzheimer’s Diseasementioning

confidence: 99%

Targeting Hsp90/Hsp70-Based Protein Quality Control for Treatment of Adult Onset Neurodegenerative Diseases

Pratt¹,

Gestwicki

Osawa³

et al. 2015

Annu. Rev. Pharmacol. Toxicol.

201

179

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Currently available therapies for adult onset neurodegenerative diseases provide symptomatic relief, but are not disease modifying. We explore here a new neuroprotective approach based on drugs targeting chaperone-directed protein quality control. Critical target proteins that unfold and aggregate in these diseases, such as the polylglutamine androgen receptor (spinal and bulbar muscular atrophy), huntingtin (Huntington’s disease), α-synuclein (Parkinson’s disease) and tau (Alzheimer’s disease) are client proteins of Hsp90, and their turnover is regulated by the protein quality control function of the Hsp90/Hsp70-based chaperone machinery. In protein quality control Hsp90 and Hsp70 have opposing effects on client protein stability; Hsp90 stabilizes the clients and inhibits their ubiquitination, whereas Hsp70 promotes CHIP-dependent ubiquitination and proteasomal degradation. We discuss how drugs that modulate proteostasis by inhibiting Hsp90 function or by promoting Hsp70 function enhance the degradation of the critical aggregating proteins and ameliorate toxic symptoms in cell and animal disease models.

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Drosophila models of human tauopathies indicate that Tau protein toxicity in vivo is mediated by soluble cytosolic phosphorylated forms of the protein

Cited by 69 publications

References 31 publications

Elevated Levels of Soluble Total and Hyperphosphorylated Tau Result in Early Behavioral Deficits and Distinct Changes in Brain Pathology in a New Tau Transgenic Mouse Model

Elevated Levels of Soluble Total and Hyperphosphorylated Tau Result in Early Behavioral Deficits and Distinct Changes in Brain Pathology in a New Tau Transgenic Mouse Model

The Power and Richness of Modelling Tauopathies in Drosophila

Targeting Hsp90/Hsp70-Based Protein Quality Control for Treatment of Adult Onset Neurodegenerative Diseases

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