Regenerating islet-derived 1α (REG-1α) protein increases tau phosphorylation in cell and animal models of tauopathies

Moussaed, Mireille; Huc-Brandt, Sylvaine; Cubedo, Nicolas; Silhol, Michelle; Murat, Samy; Lebart, Marie‐Christine; Kovács, Gábor G.; Verdier, Jean‐Michel; Trousse, Françoise; Rossel, Mireille; Marcilhac, Anne

doi:10.1016/j.nbd.2018.07.029

Cited by 9 publications

(16 citation statements)

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“…Furthermore, activation of the β-catenin pathway in mESCs has been linked to the specific up-regulation and secretion of Reg-1α. Notably, in cortical neurons that express Tau P301L and thus present alterations in the microtubule network, Reg-1α induces GSK-3β activation (Moussaed et al, 2018). Nevertheless, the link between Reg-1α and Wnt signaling in vivo needs to be further clarified.…”

Section: Discussionmentioning

confidence: 99%

“…Primary antibodies were: rabbit anti-Reg-1α [1:500 ( Duplan et al, 2001 )], goat anti-EXTL3 (1:1000, #AF2635, R&D Systems), rabbit anti-p-GSK-3β Ser 9 (1:1000,#9336S, Cell Signaling); mouse anti-GSK-3β (1:5000, # 610201, BD Transduction laboratory), mouse anti-p-GSK-3β Tyr 216 (1:1000, # 612313, BD Transduction laboratory) anti-β-catenin (1:5000,#610153, BD Transduction laboratory) and mouse anti-β-actin (1:5000,#A5441, Sigma-Aldrich). Generation and specificity of the anti-Reg-1α rabbit polyclonal antibody has been previously reported ( Duplan et al, 2001 ; Laurine et al, 2003 ; Acquatella-Tran Van Ba et al, 2012 ; Moussaed et al, 2018 ).…”

Section: Methodsmentioning

confidence: 99%

“…(1:5000,#610153, BD Transduction laboratory) and mouse anti-β-actin (1:5000,#A5441, Sigma-Aldrich). Generation and specificity of the anti-Reg-1α rabbit polyclonal antibody has been previously reported (Duplan et al, 2001;Laurine et al, 2003;Acquatella-Tran Van Ba et al, 2012;Moussaed et al, 2018).…”

Section: Genementioning

confidence: 99%

“…Reg-1α regulates GSK-3β (Moussaed et al, 2018) and GSK-3β/β-catenin signaling is known to play a key role in stem cell migration and differentiation. We thus asked whether the observed Reg-1α effects were mediated via this pathway.…”

Section: Cross-talk Between Reg-1α and Gsk3-β Pathwaymentioning

confidence: 99%

“…Reg-1α colocalizes with hyperphosphorylated Tau in neurofibrillary tangles from AD and progressive supranuclear palsy (PSP) brains. Furthermore, in cellular tauopathy models, Reg-1α increases Tau phosphorylation via AKT/GSK-3β pathway leading to morphological abnormalities of neurons and axonal transport defects (Moussaed et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Reg-1α Promotes Differentiation of Cortical Progenitors via Its N-Terminal Active Domain

Varilh

Silhol

et al. 2020

Front. Cell Dev. Biol.

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Reg-1α belongs to the Reg family of small, secreted proteins expressed in both pancreas and nervous system. Reg-1α is composed of two domains, an insoluble C-type lectin domain and a short soluble N-terminal peptide, which is released from the molecule upon proteolytic N-terminal processing, although the biological significance of this proteolysis remains unclear. We have previously shown that binding of Reg-1α to its receptor Extl3 stimulates axonal outgrowth. Reg-1α and Extl3 genes are expressed in the developing cortex but their expression decreases in adulthood, pointing to a possible function of this signaling system at the early developmental stages. Here, we demonstrate that recombinant Reg-1α increases migration and differentiation of cultured embryonic rat telencephalic progenitors via the activation of GSK-3β activity. In vivo overexpression of Reg-1α by in utero electroporation, has a similar effect, favoring premature differentiation of cortical progenitors. Notably, the N-terminal soluble domain, but not the C-type lectin domain, is largely responsible for Reg-1α effects on cortical neuronal differentiation. We thus conclude that Reg-1α via its proteolytically generated N-terminal domain is required for basic development processes.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Genementioning

confidence: 99%

Section: Cross-talk Between Reg-1α and Gsk3-β Pathwaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Reg-1α Promotes Differentiation of Cortical Progenitors via Its N-Terminal Active Domain

Varilh

Silhol

et al. 2020

Front. Cell Dev. Biol.

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Localization, induction, and cellular effects of tau phosphorylated at threonine 217¹

Rajbanshi

Guruacharya

Mandell

et al. 2023

Alzheimer's & Dementia

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Introduction: Tau phosphorylation at T217 is a promising Alzheimer's disease (AD) biomarker, but its functional consequences were unknown.Methods: Human brain and cultured mouse neurons were analyzed by immunoblotting and immunofluorescence for total tau, tau pT217 , tau pT181 , tau pT231 , and tau pS396/pS404 . Direct stochastic optical reconstruction microscopy (dSTORM) super resolution microscopy was used to localize tau pT217 in cultured neurons. Enhanced green fluorescent protein (EGFP)-tau was expressed in fibroblasts as wild type and T217E pseudo-phosphorylated tau, and fluorescence recovery after photobleaching (FRAP) reported tau turnover rates on microtubules. Results:In the brain, tau pT217 appears in neurons at Braak stages I and II, becomes more prevalent later, and co-localizes partially with other phospho-tau epitopes. In cultured neurons, tau pT217 is increased by extracellular tau oligomers (xcTauOs) and is associated with developing post-synaptic sites. FRAP recovery was fastest for EGFP-tau T217E . Conclusion:Tau pT217 increases in the brain as AD progresses and is induced by xcTauOs. Post-synaptic tau pT217 suggests a role for T217 phosphorylation in synapse impairment. T217 phosphorylation reduces tau's affinity for microtubules.

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Localization, induction, and cellular effects of tau-phospho-threonine 217

Rajbanshi

Mandell

Bloom

2022

Preprint

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IntroductionTau phosphorylation at T217 is a promising AD biomarker, but its functional consequences were unknown.MethodsHuman brain and cultured mouse neurons were analyzed by immunoblotting and immunofluorescence for total tau, taupT217, taupT181, taupT231 and taupS396/pS404. dSTORM super resolution microscopy was used to localize taupT217 in cultured neurons. EGFP-tau was expressed in fibroblasts as wild type and T217E pseudo-phosphorylated tau, and fluorescence recovery after photobleaching (FRAP) reported tau turnover rates on microtubules.ResultsIn brain, taupT217 appears in neurons at Braak stages I-II, becomes more prevalent later and co-localizes partially with other phospho-tau epitopes. In cultured neurons taupT217, is increased by extracellular tau oligomers (xcTauOs), and is associated with developing post-synaptic sites. FRAP recovery was fastest for EGFP-tauT217E.ConclusionTaupT217 increases in brain as AD progresses and is induced by xcTauOs. Post-synaptic taupT217 suggests a role for T217 phosphorylation in synapse impairment. T217 phosphorylation reduces tau’s affinity for microtubules.

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Regenerating islet-derived 1α (REG-1α) protein increases tau phosphorylation in cell and animal models of tauopathies

Cited by 9 publications

References 35 publications

Reg-1α Promotes Differentiation of Cortical Progenitors via Its N-Terminal Active Domain

Reg-1α Promotes Differentiation of Cortical Progenitors via Its N-Terminal Active Domain

Localization, induction, and cellular effects of tau phosphorylated at threonine 217¹

Localization, induction, and cellular effects of tau-phospho-threonine 217

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Regenerating islet-derived 1α (REG-1α) protein increases tau phosphorylation in cell and animal models of tauopathies

Cited by 9 publications

References 35 publications

Reg-1α Promotes Differentiation of Cortical Progenitors via Its N-Terminal Active Domain

Reg-1α Promotes Differentiation of Cortical Progenitors via Its N-Terminal Active Domain

Localization, induction, and cellular effects of tau phosphorylated at threonine 2171

Localization, induction, and cellular effects of tau-phospho-threonine 217

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Localization, induction, and cellular effects of tau phosphorylated at threonine 217¹