A pathogenic tau fragment compromises microtubules, disrupts insulin signaling and induces the unfolded protein response

Abstract Human tauopathies including Alzheimer’s disease, progressive supranuclear palsy and related disorders, are characterized by deposition of pathological forms of tau, synaptic dysfunction and neuronal loss. We have previously identified a pathogenic C-terminal tau fragment (Tau35) that is associated with human tauopathy. However, it is not known how tau fragmentation affects critical molecular processes in cells and contributes to impaired physiological function. Chinese hamster ovary (CHO) cells and new CHO cell lines stably expressing Tau35 or full-length human tau were used to compare the effects of disease-associated tau cleavage on tau function and signaling pathways. Western blots, microtubule-binding assays and immunofluorescence labeling were used to examine the effects of Tau35 on tau function and on signaling pathways in CHO cells. We show that Tau35 undergoes aberrant phosphorylation when expressed in cells. Although Tau35 contain the entire microtubule-binding region, the lack of the amino terminal half of tau results in a marked reduction in microtubule binding and defective microtubule organization in cells. Notably, Tau35 attenuates insulin-mediated activation of Akt and a selective inhibitory phosphorylation of glycogen synthase kinase-3. Moreover, Tau35 activates ribosomal protein S6 kinase beta-1 signaling and the unfolded protein response, leading to insulin resistance in cells. Tau35 has deleterious effects on signaling pathways that mediate pathological changes and insulin resistance, suggesting a mechanism through which N-terminal cleavage of tau leads to the development and progression of tau pathology in human tauopathy. Our findings highlight the importance of the N-terminal region of tau for its normal physiological function. Furthermore, we show that pathogenic tau cleavage induces tau phosphorylation, resulting in impaired microtubule binding, disruption of insulin signaling and activation of the unfolded protein response. Since insulin resistance is a feature of several tauopathies, this work suggests new potential targets for therapeutic intervention. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Guo, Tong [verfasserIn] Dakkak, Dina Rodriguez-Martin, Teresa Noble, Wendy Hanger, Diane P.

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2019

Schlagwörter:	Tau Tauopathy Microtubule binding Akt Glycogen synthase kinase-3 Insulin Unfolded protein response

Anmerkung:	© The Author(s). 2019

Übergeordnetes Werk:	Enthalten in: Acta Neuropathologica Communications - London : Biomed Central, 2013, 7(2019), 1 vom: 03. Jan.
Übergeordnetes Werk:	volume:7 ; year:2019 ; number:1 ; day:03 ; month:01

Links:	Volltext

DOI / URN:	10.1186/s40478-018-0651-9

Katalog-ID:	SPR036514454

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allfields	10.1186/s40478-018-0651-9 doi (DE-627)SPR036514454 (SPR)s40478-018-0651-9-e DE-627 ger DE-627 rakwb eng Guo, Tong verfasserin aut A pathogenic tau fragment compromises microtubules, disrupts insulin signaling and induces the unfolded protein response 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2019 Abstract Human tauopathies including Alzheimer’s disease, progressive supranuclear palsy and related disorders, are characterized by deposition of pathological forms of tau, synaptic dysfunction and neuronal loss. We have previously identified a pathogenic C-terminal tau fragment (Tau35) that is associated with human tauopathy. However, it is not known how tau fragmentation affects critical molecular processes in cells and contributes to impaired physiological function. Chinese hamster ovary (CHO) cells and new CHO cell lines stably expressing Tau35 or full-length human tau were used to compare the effects of disease-associated tau cleavage on tau function and signaling pathways. Western blots, microtubule-binding assays and immunofluorescence labeling were used to examine the effects of Tau35 on tau function and on signaling pathways in CHO cells. We show that Tau35 undergoes aberrant phosphorylation when expressed in cells. Although Tau35 contain the entire microtubule-binding region, the lack of the amino terminal half of tau results in a marked reduction in microtubule binding and defective microtubule organization in cells. Notably, Tau35 attenuates insulin-mediated activation of Akt and a selective inhibitory phosphorylation of glycogen synthase kinase-3. Moreover, Tau35 activates ribosomal protein S6 kinase beta-1 signaling and the unfolded protein response, leading to insulin resistance in cells. Tau35 has deleterious effects on signaling pathways that mediate pathological changes and insulin resistance, suggesting a mechanism through which N-terminal cleavage of tau leads to the development and progression of tau pathology in human tauopathy. Our findings highlight the importance of the N-terminal region of tau for its normal physiological function. Furthermore, we show that pathogenic tau cleavage induces tau phosphorylation, resulting in impaired microtubule binding, disruption of insulin signaling and activation of the unfolded protein response. Since insulin resistance is a feature of several tauopathies, this work suggests new potential targets for therapeutic intervention. Tau (dpeaa)DE-He213 Tauopathy (dpeaa)DE-He213 Microtubule binding (dpeaa)DE-He213 Akt (dpeaa)DE-He213 Glycogen synthase kinase-3 (dpeaa)DE-He213 Insulin (dpeaa)DE-He213 Unfolded protein response (dpeaa)DE-He213 Dakkak, Dina aut Rodriguez-Martin, Teresa aut Noble, Wendy aut Hanger, Diane P. (orcid)0000-0002-3044-9816 aut Enthalten in Acta Neuropathologica Communications London : Biomed Central, 2013 7(2019), 1 vom: 03. Jan. (DE-627)746066465 (DE-600)2715589-4 2051-5960 nnns volume:7 year:2019 number:1 day:03 month:01 https://dx.doi.org/10.1186/s40478-018-0651-9 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2019 1 03 01
spelling	10.1186/s40478-018-0651-9 doi (DE-627)SPR036514454 (SPR)s40478-018-0651-9-e DE-627 ger DE-627 rakwb eng Guo, Tong verfasserin aut A pathogenic tau fragment compromises microtubules, disrupts insulin signaling and induces the unfolded protein response 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2019 Abstract Human tauopathies including Alzheimer’s disease, progressive supranuclear palsy and related disorders, are characterized by deposition of pathological forms of tau, synaptic dysfunction and neuronal loss. We have previously identified a pathogenic C-terminal tau fragment (Tau35) that is associated with human tauopathy. However, it is not known how tau fragmentation affects critical molecular processes in cells and contributes to impaired physiological function. Chinese hamster ovary (CHO) cells and new CHO cell lines stably expressing Tau35 or full-length human tau were used to compare the effects of disease-associated tau cleavage on tau function and signaling pathways. Western blots, microtubule-binding assays and immunofluorescence labeling were used to examine the effects of Tau35 on tau function and on signaling pathways in CHO cells. We show that Tau35 undergoes aberrant phosphorylation when expressed in cells. Although Tau35 contain the entire microtubule-binding region, the lack of the amino terminal half of tau results in a marked reduction in microtubule binding and defective microtubule organization in cells. Notably, Tau35 attenuates insulin-mediated activation of Akt and a selective inhibitory phosphorylation of glycogen synthase kinase-3. Moreover, Tau35 activates ribosomal protein S6 kinase beta-1 signaling and the unfolded protein response, leading to insulin resistance in cells. Tau35 has deleterious effects on signaling pathways that mediate pathological changes and insulin resistance, suggesting a mechanism through which N-terminal cleavage of tau leads to the development and progression of tau pathology in human tauopathy. Our findings highlight the importance of the N-terminal region of tau for its normal physiological function. Furthermore, we show that pathogenic tau cleavage induces tau phosphorylation, resulting in impaired microtubule binding, disruption of insulin signaling and activation of the unfolded protein response. Since insulin resistance is a feature of several tauopathies, this work suggests new potential targets for therapeutic intervention. Tau (dpeaa)DE-He213 Tauopathy (dpeaa)DE-He213 Microtubule binding (dpeaa)DE-He213 Akt (dpeaa)DE-He213 Glycogen synthase kinase-3 (dpeaa)DE-He213 Insulin (dpeaa)DE-He213 Unfolded protein response (dpeaa)DE-He213 Dakkak, Dina aut Rodriguez-Martin, Teresa aut Noble, Wendy aut Hanger, Diane P. (orcid)0000-0002-3044-9816 aut Enthalten in Acta Neuropathologica Communications London : Biomed Central, 2013 7(2019), 1 vom: 03. Jan. (DE-627)746066465 (DE-600)2715589-4 2051-5960 nnns volume:7 year:2019 number:1 day:03 month:01 https://dx.doi.org/10.1186/s40478-018-0651-9 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2019 1 03 01
allfields_unstemmed	10.1186/s40478-018-0651-9 doi (DE-627)SPR036514454 (SPR)s40478-018-0651-9-e DE-627 ger DE-627 rakwb eng Guo, Tong verfasserin aut A pathogenic tau fragment compromises microtubules, disrupts insulin signaling and induces the unfolded protein response 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2019 Abstract Human tauopathies including Alzheimer’s disease, progressive supranuclear palsy and related disorders, are characterized by deposition of pathological forms of tau, synaptic dysfunction and neuronal loss. We have previously identified a pathogenic C-terminal tau fragment (Tau35) that is associated with human tauopathy. However, it is not known how tau fragmentation affects critical molecular processes in cells and contributes to impaired physiological function. Chinese hamster ovary (CHO) cells and new CHO cell lines stably expressing Tau35 or full-length human tau were used to compare the effects of disease-associated tau cleavage on tau function and signaling pathways. Western blots, microtubule-binding assays and immunofluorescence labeling were used to examine the effects of Tau35 on tau function and on signaling pathways in CHO cells. We show that Tau35 undergoes aberrant phosphorylation when expressed in cells. Although Tau35 contain the entire microtubule-binding region, the lack of the amino terminal half of tau results in a marked reduction in microtubule binding and defective microtubule organization in cells. Notably, Tau35 attenuates insulin-mediated activation of Akt and a selective inhibitory phosphorylation of glycogen synthase kinase-3. Moreover, Tau35 activates ribosomal protein S6 kinase beta-1 signaling and the unfolded protein response, leading to insulin resistance in cells. Tau35 has deleterious effects on signaling pathways that mediate pathological changes and insulin resistance, suggesting a mechanism through which N-terminal cleavage of tau leads to the development and progression of tau pathology in human tauopathy. Our findings highlight the importance of the N-terminal region of tau for its normal physiological function. Furthermore, we show that pathogenic tau cleavage induces tau phosphorylation, resulting in impaired microtubule binding, disruption of insulin signaling and activation of the unfolded protein response. Since insulin resistance is a feature of several tauopathies, this work suggests new potential targets for therapeutic intervention. Tau (dpeaa)DE-He213 Tauopathy (dpeaa)DE-He213 Microtubule binding (dpeaa)DE-He213 Akt (dpeaa)DE-He213 Glycogen synthase kinase-3 (dpeaa)DE-He213 Insulin (dpeaa)DE-He213 Unfolded protein response (dpeaa)DE-He213 Dakkak, Dina aut Rodriguez-Martin, Teresa aut Noble, Wendy aut Hanger, Diane P. (orcid)0000-0002-3044-9816 aut Enthalten in Acta Neuropathologica Communications London : Biomed Central, 2013 7(2019), 1 vom: 03. Jan. (DE-627)746066465 (DE-600)2715589-4 2051-5960 nnns volume:7 year:2019 number:1 day:03 month:01 https://dx.doi.org/10.1186/s40478-018-0651-9 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2019 1 03 01
allfieldsGer	10.1186/s40478-018-0651-9 doi (DE-627)SPR036514454 (SPR)s40478-018-0651-9-e DE-627 ger DE-627 rakwb eng Guo, Tong verfasserin aut A pathogenic tau fragment compromises microtubules, disrupts insulin signaling and induces the unfolded protein response 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2019 Abstract Human tauopathies including Alzheimer’s disease, progressive supranuclear palsy and related disorders, are characterized by deposition of pathological forms of tau, synaptic dysfunction and neuronal loss. We have previously identified a pathogenic C-terminal tau fragment (Tau35) that is associated with human tauopathy. However, it is not known how tau fragmentation affects critical molecular processes in cells and contributes to impaired physiological function. Chinese hamster ovary (CHO) cells and new CHO cell lines stably expressing Tau35 or full-length human tau were used to compare the effects of disease-associated tau cleavage on tau function and signaling pathways. Western blots, microtubule-binding assays and immunofluorescence labeling were used to examine the effects of Tau35 on tau function and on signaling pathways in CHO cells. We show that Tau35 undergoes aberrant phosphorylation when expressed in cells. Although Tau35 contain the entire microtubule-binding region, the lack of the amino terminal half of tau results in a marked reduction in microtubule binding and defective microtubule organization in cells. Notably, Tau35 attenuates insulin-mediated activation of Akt and a selective inhibitory phosphorylation of glycogen synthase kinase-3. Moreover, Tau35 activates ribosomal protein S6 kinase beta-1 signaling and the unfolded protein response, leading to insulin resistance in cells. Tau35 has deleterious effects on signaling pathways that mediate pathological changes and insulin resistance, suggesting a mechanism through which N-terminal cleavage of tau leads to the development and progression of tau pathology in human tauopathy. Our findings highlight the importance of the N-terminal region of tau for its normal physiological function. Furthermore, we show that pathogenic tau cleavage induces tau phosphorylation, resulting in impaired microtubule binding, disruption of insulin signaling and activation of the unfolded protein response. Since insulin resistance is a feature of several tauopathies, this work suggests new potential targets for therapeutic intervention. Tau (dpeaa)DE-He213 Tauopathy (dpeaa)DE-He213 Microtubule binding (dpeaa)DE-He213 Akt (dpeaa)DE-He213 Glycogen synthase kinase-3 (dpeaa)DE-He213 Insulin (dpeaa)DE-He213 Unfolded protein response (dpeaa)DE-He213 Dakkak, Dina aut Rodriguez-Martin, Teresa aut Noble, Wendy aut Hanger, Diane P. (orcid)0000-0002-3044-9816 aut Enthalten in Acta Neuropathologica Communications London : Biomed Central, 2013 7(2019), 1 vom: 03. Jan. (DE-627)746066465 (DE-600)2715589-4 2051-5960 nnns volume:7 year:2019 number:1 day:03 month:01 https://dx.doi.org/10.1186/s40478-018-0651-9 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2019 1 03 01
allfieldsSound	10.1186/s40478-018-0651-9 doi (DE-627)SPR036514454 (SPR)s40478-018-0651-9-e DE-627 ger DE-627 rakwb eng Guo, Tong verfasserin aut A pathogenic tau fragment compromises microtubules, disrupts insulin signaling and induces the unfolded protein response 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2019 Abstract Human tauopathies including Alzheimer’s disease, progressive supranuclear palsy and related disorders, are characterized by deposition of pathological forms of tau, synaptic dysfunction and neuronal loss. We have previously identified a pathogenic C-terminal tau fragment (Tau35) that is associated with human tauopathy. However, it is not known how tau fragmentation affects critical molecular processes in cells and contributes to impaired physiological function. Chinese hamster ovary (CHO) cells and new CHO cell lines stably expressing Tau35 or full-length human tau were used to compare the effects of disease-associated tau cleavage on tau function and signaling pathways. Western blots, microtubule-binding assays and immunofluorescence labeling were used to examine the effects of Tau35 on tau function and on signaling pathways in CHO cells. We show that Tau35 undergoes aberrant phosphorylation when expressed in cells. Although Tau35 contain the entire microtubule-binding region, the lack of the amino terminal half of tau results in a marked reduction in microtubule binding and defective microtubule organization in cells. Notably, Tau35 attenuates insulin-mediated activation of Akt and a selective inhibitory phosphorylation of glycogen synthase kinase-3. Moreover, Tau35 activates ribosomal protein S6 kinase beta-1 signaling and the unfolded protein response, leading to insulin resistance in cells. Tau35 has deleterious effects on signaling pathways that mediate pathological changes and insulin resistance, suggesting a mechanism through which N-terminal cleavage of tau leads to the development and progression of tau pathology in human tauopathy. Our findings highlight the importance of the N-terminal region of tau for its normal physiological function. Furthermore, we show that pathogenic tau cleavage induces tau phosphorylation, resulting in impaired microtubule binding, disruption of insulin signaling and activation of the unfolded protein response. Since insulin resistance is a feature of several tauopathies, this work suggests new potential targets for therapeutic intervention. Tau (dpeaa)DE-He213 Tauopathy (dpeaa)DE-He213 Microtubule binding (dpeaa)DE-He213 Akt (dpeaa)DE-He213 Glycogen synthase kinase-3 (dpeaa)DE-He213 Insulin (dpeaa)DE-He213 Unfolded protein response (dpeaa)DE-He213 Dakkak, Dina aut Rodriguez-Martin, Teresa aut Noble, Wendy aut Hanger, Diane P. (orcid)0000-0002-3044-9816 aut Enthalten in Acta Neuropathologica Communications London : Biomed Central, 2013 7(2019), 1 vom: 03. Jan. (DE-627)746066465 (DE-600)2715589-4 2051-5960 nnns volume:7 year:2019 number:1 day:03 month:01 https://dx.doi.org/10.1186/s40478-018-0651-9 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2019 1 03 01
language	English
source	Enthalten in Acta Neuropathologica Communications 7(2019), 1 vom: 03. Jan. volume:7 year:2019 number:1 day:03 month:01
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author	Guo, Tong
spellingShingle	Guo, Tong misc Tau misc Tauopathy misc Microtubule binding misc Akt misc Glycogen synthase kinase-3 misc Insulin misc Unfolded protein response A pathogenic tau fragment compromises microtubules, disrupts insulin signaling and induces the unfolded protein response
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topic_title	A pathogenic tau fragment compromises microtubules, disrupts insulin signaling and induces the unfolded protein response Tau (dpeaa)DE-He213 Tauopathy (dpeaa)DE-He213 Microtubule binding (dpeaa)DE-He213 Akt (dpeaa)DE-He213 Glycogen synthase kinase-3 (dpeaa)DE-He213 Insulin (dpeaa)DE-He213 Unfolded protein response (dpeaa)DE-He213
topic	misc Tau misc Tauopathy misc Microtubule binding misc Akt misc Glycogen synthase kinase-3 misc Insulin misc Unfolded protein response
topic_unstemmed	misc Tau misc Tauopathy misc Microtubule binding misc Akt misc Glycogen synthase kinase-3 misc Insulin misc Unfolded protein response
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title	A pathogenic tau fragment compromises microtubules, disrupts insulin signaling and induces the unfolded protein response
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title_sort	pathogenic tau fragment compromises microtubules, disrupts insulin signaling and induces the unfolded protein response
title_auth	A pathogenic tau fragment compromises microtubules, disrupts insulin signaling and induces the unfolded protein response
abstract	Abstract Human tauopathies including Alzheimer’s disease, progressive supranuclear palsy and related disorders, are characterized by deposition of pathological forms of tau, synaptic dysfunction and neuronal loss. We have previously identified a pathogenic C-terminal tau fragment (Tau35) that is associated with human tauopathy. However, it is not known how tau fragmentation affects critical molecular processes in cells and contributes to impaired physiological function. Chinese hamster ovary (CHO) cells and new CHO cell lines stably expressing Tau35 or full-length human tau were used to compare the effects of disease-associated tau cleavage on tau function and signaling pathways. Western blots, microtubule-binding assays and immunofluorescence labeling were used to examine the effects of Tau35 on tau function and on signaling pathways in CHO cells. We show that Tau35 undergoes aberrant phosphorylation when expressed in cells. Although Tau35 contain the entire microtubule-binding region, the lack of the amino terminal half of tau results in a marked reduction in microtubule binding and defective microtubule organization in cells. Notably, Tau35 attenuates insulin-mediated activation of Akt and a selective inhibitory phosphorylation of glycogen synthase kinase-3. Moreover, Tau35 activates ribosomal protein S6 kinase beta-1 signaling and the unfolded protein response, leading to insulin resistance in cells. Tau35 has deleterious effects on signaling pathways that mediate pathological changes and insulin resistance, suggesting a mechanism through which N-terminal cleavage of tau leads to the development and progression of tau pathology in human tauopathy. Our findings highlight the importance of the N-terminal region of tau for its normal physiological function. Furthermore, we show that pathogenic tau cleavage induces tau phosphorylation, resulting in impaired microtubule binding, disruption of insulin signaling and activation of the unfolded protein response. Since insulin resistance is a feature of several tauopathies, this work suggests new potential targets for therapeutic intervention. © The Author(s). 2019
abstractGer	Abstract Human tauopathies including Alzheimer’s disease, progressive supranuclear palsy and related disorders, are characterized by deposition of pathological forms of tau, synaptic dysfunction and neuronal loss. We have previously identified a pathogenic C-terminal tau fragment (Tau35) that is associated with human tauopathy. However, it is not known how tau fragmentation affects critical molecular processes in cells and contributes to impaired physiological function. Chinese hamster ovary (CHO) cells and new CHO cell lines stably expressing Tau35 or full-length human tau were used to compare the effects of disease-associated tau cleavage on tau function and signaling pathways. Western blots, microtubule-binding assays and immunofluorescence labeling were used to examine the effects of Tau35 on tau function and on signaling pathways in CHO cells. We show that Tau35 undergoes aberrant phosphorylation when expressed in cells. Although Tau35 contain the entire microtubule-binding region, the lack of the amino terminal half of tau results in a marked reduction in microtubule binding and defective microtubule organization in cells. Notably, Tau35 attenuates insulin-mediated activation of Akt and a selective inhibitory phosphorylation of glycogen synthase kinase-3. Moreover, Tau35 activates ribosomal protein S6 kinase beta-1 signaling and the unfolded protein response, leading to insulin resistance in cells. Tau35 has deleterious effects on signaling pathways that mediate pathological changes and insulin resistance, suggesting a mechanism through which N-terminal cleavage of tau leads to the development and progression of tau pathology in human tauopathy. Our findings highlight the importance of the N-terminal region of tau for its normal physiological function. Furthermore, we show that pathogenic tau cleavage induces tau phosphorylation, resulting in impaired microtubule binding, disruption of insulin signaling and activation of the unfolded protein response. Since insulin resistance is a feature of several tauopathies, this work suggests new potential targets for therapeutic intervention. © The Author(s). 2019
abstract_unstemmed	Abstract Human tauopathies including Alzheimer’s disease, progressive supranuclear palsy and related disorders, are characterized by deposition of pathological forms of tau, synaptic dysfunction and neuronal loss. We have previously identified a pathogenic C-terminal tau fragment (Tau35) that is associated with human tauopathy. However, it is not known how tau fragmentation affects critical molecular processes in cells and contributes to impaired physiological function. Chinese hamster ovary (CHO) cells and new CHO cell lines stably expressing Tau35 or full-length human tau were used to compare the effects of disease-associated tau cleavage on tau function and signaling pathways. Western blots, microtubule-binding assays and immunofluorescence labeling were used to examine the effects of Tau35 on tau function and on signaling pathways in CHO cells. We show that Tau35 undergoes aberrant phosphorylation when expressed in cells. Although Tau35 contain the entire microtubule-binding region, the lack of the amino terminal half of tau results in a marked reduction in microtubule binding and defective microtubule organization in cells. Notably, Tau35 attenuates insulin-mediated activation of Akt and a selective inhibitory phosphorylation of glycogen synthase kinase-3. Moreover, Tau35 activates ribosomal protein S6 kinase beta-1 signaling and the unfolded protein response, leading to insulin resistance in cells. Tau35 has deleterious effects on signaling pathways that mediate pathological changes and insulin resistance, suggesting a mechanism through which N-terminal cleavage of tau leads to the development and progression of tau pathology in human tauopathy. Our findings highlight the importance of the N-terminal region of tau for its normal physiological function. Furthermore, we show that pathogenic tau cleavage induces tau phosphorylation, resulting in impaired microtubule binding, disruption of insulin signaling and activation of the unfolded protein response. Since insulin resistance is a feature of several tauopathies, this work suggests new potential targets for therapeutic intervention. © The Author(s). 2019
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We have previously identified a pathogenic C-terminal tau fragment (Tau35) that is associated with human tauopathy. However, it is not known how tau fragmentation affects critical molecular processes in cells and contributes to impaired physiological function. Chinese hamster ovary (CHO) cells and new CHO cell lines stably expressing Tau35 or full-length human tau were used to compare the effects of disease-associated tau cleavage on tau function and signaling pathways. Western blots, microtubule-binding assays and immunofluorescence labeling were used to examine the effects of Tau35 on tau function and on signaling pathways in CHO cells. We show that Tau35 undergoes aberrant phosphorylation when expressed in cells. Although Tau35 contain the entire microtubule-binding region, the lack of the amino terminal half of tau results in a marked reduction in microtubule binding and defective microtubule organization in cells. Notably, Tau35 attenuates insulin-mediated activation of Akt and a selective inhibitory phosphorylation of glycogen synthase kinase-3. Moreover, Tau35 activates ribosomal protein S6 kinase beta-1 signaling and the unfolded protein response, leading to insulin resistance in cells. Tau35 has deleterious effects on signaling pathways that mediate pathological changes and insulin resistance, suggesting a mechanism through which N-terminal cleavage of tau leads to the development and progression of tau pathology in human tauopathy. Our findings highlight the importance of the N-terminal region of tau for its normal physiological function. Furthermore, we show that pathogenic tau cleavage induces tau phosphorylation, resulting in impaired microtubule binding, disruption of insulin signaling and activation of the unfolded protein response. Since insulin resistance is a feature of several tauopathies, this work suggests new potential targets for therapeutic intervention.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Tau</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Tauopathy</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Microtubule binding</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Akt</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Glycogen synthase kinase-3</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Insulin</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Unfolded protein response</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Dakkak, Dina</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Rodriguez-Martin, Teresa</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Noble, Wendy</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Hanger, Diane P.</subfield><subfield code="0">(orcid)0000-0002-3044-9816</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">Acta Neuropathologica Communications</subfield><subfield code="d">London : Biomed Central, 2013</subfield><subfield code="g">7(2019), 1 vom: 03. 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A pathogenic tau fragment compromises microtubules, disrupts insulin signaling and induces the unfolded protein response

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