Novel repertoire of tau biosensors to monitor pathological tau transformation and seeding activity in living cells
Aggregates of the tau protein are a well-known hallmark of several neurodegenerative diseases, collectively referred to as tauopathies, including frontal temporal dementia and Alzheimer’s disease (AD). Monitoring the transformation process of tau from physiological monomers into pathological oligome...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-03-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/78360 |
| _version_ | 1797870933732491264 |
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| author | Erika Cecon Atsuro Oishi Marine Luka Delphine Ndiaye-Lobry Arnaud François Mathias Lescuyer Fany Panayi Julie Dam Patricia Machado Ralf Jockers |
| author_facet | Erika Cecon Atsuro Oishi Marine Luka Delphine Ndiaye-Lobry Arnaud François Mathias Lescuyer Fany Panayi Julie Dam Patricia Machado Ralf Jockers |
| author_sort | Erika Cecon |
| collection | DOAJ |
| description | Aggregates of the tau protein are a well-known hallmark of several neurodegenerative diseases, collectively referred to as tauopathies, including frontal temporal dementia and Alzheimer’s disease (AD). Monitoring the transformation process of tau from physiological monomers into pathological oligomers or aggregates in a high-throughput, quantitative manner and in a cellular context is still a major challenge in the field. Identifying molecules able to interfere with those processes is of high therapeutic interest. Here, we developed a series of inter- and intramolecular tau biosensors based on the highly sensitive Nanoluciferase (Nluc) binary technology (NanoBiT) able to monitor the pathological conformational change and self-interaction of tau in living cells. Our repertoire of tau biosensors reliably reports i. molecular proximity of physiological full-length tau at microtubules; ii. changes in tau conformation and self-interaction associated with tau phosphorylation, as well as iii. tau interaction induced by seeds of recombinant tau or from mouse brain lysates of a mouse model of tau pathology. By comparing biosensors comprising different tau forms (i.e. full-length or short fragments, wild-type, or the disease-associated tau(P301L) variant) further insights into the tau transformation process are obtained. Proof-of-concept data for the high-throughput suitability and identification of molecules interfering with the pathological tau transformation processes are presented. This novel repertoire of tau biosensors is aimed to boost the disclosure of molecular mechanisms underlying pathological tau transformation in living cells and to discover new drug candidates for tau-related neurodegenerative diseases. |
| first_indexed | 2024-04-10T00:36:18Z |
| format | Article |
| id | doaj.art-60b46b54a6b242a9afabff8b315dade9 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-10T00:36:18Z |
| publishDate | 2023-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-60b46b54a6b242a9afabff8b315dade92023-03-14T16:26:16ZengeLife Sciences Publications LtdeLife2050-084X2023-03-011210.7554/eLife.78360Novel repertoire of tau biosensors to monitor pathological tau transformation and seeding activity in living cellsErika Cecon0https://orcid.org/0000-0003-2387-9313Atsuro Oishi1https://orcid.org/0000-0003-1788-5485Marine Luka2Delphine Ndiaye-Lobry3Arnaud François4Mathias Lescuyer5Fany Panayi6Julie Dam7Patricia Machado8Ralf Jockers9https://orcid.org/0000-0002-4354-1750Institut Cochin, Inserm U1016, CNRS UMR 8104, Université de Paris, Paris, FranceInstitut Cochin, Inserm U1016, CNRS UMR 8104, Université de Paris, Paris, FranceInstitut Cochin, Inserm U1016, CNRS UMR 8104, Université de Paris, Paris, FranceInstitut Cochin, Inserm U1016, CNRS UMR 8104, Université de Paris, Paris, FranceLes Laboratoires Servier, Suresnes, FranceInstitut Cochin, Inserm U1016, CNRS UMR 8104, Université de Paris, Paris, FranceLes Laboratoires Servier, Suresnes, FranceInstitut Cochin, Inserm U1016, CNRS UMR 8104, Université de Paris, Paris, FranceLes Laboratoires Servier, Suresnes, FranceInstitut Cochin, Inserm U1016, CNRS UMR 8104, Université de Paris, Paris, FranceAggregates of the tau protein are a well-known hallmark of several neurodegenerative diseases, collectively referred to as tauopathies, including frontal temporal dementia and Alzheimer’s disease (AD). Monitoring the transformation process of tau from physiological monomers into pathological oligomers or aggregates in a high-throughput, quantitative manner and in a cellular context is still a major challenge in the field. Identifying molecules able to interfere with those processes is of high therapeutic interest. Here, we developed a series of inter- and intramolecular tau biosensors based on the highly sensitive Nanoluciferase (Nluc) binary technology (NanoBiT) able to monitor the pathological conformational change and self-interaction of tau in living cells. Our repertoire of tau biosensors reliably reports i. molecular proximity of physiological full-length tau at microtubules; ii. changes in tau conformation and self-interaction associated with tau phosphorylation, as well as iii. tau interaction induced by seeds of recombinant tau or from mouse brain lysates of a mouse model of tau pathology. By comparing biosensors comprising different tau forms (i.e. full-length or short fragments, wild-type, or the disease-associated tau(P301L) variant) further insights into the tau transformation process are obtained. Proof-of-concept data for the high-throughput suitability and identification of molecules interfering with the pathological tau transformation processes are presented. This novel repertoire of tau biosensors is aimed to boost the disclosure of molecular mechanisms underlying pathological tau transformation in living cells and to discover new drug candidates for tau-related neurodegenerative diseases.https://elifesciences.org/articles/78360BiosensorsAlzheimer's diseasemicrotubulestau seedingNanoluciferase |
| spellingShingle | Erika Cecon Atsuro Oishi Marine Luka Delphine Ndiaye-Lobry Arnaud François Mathias Lescuyer Fany Panayi Julie Dam Patricia Machado Ralf Jockers Novel repertoire of tau biosensors to monitor pathological tau transformation and seeding activity in living cells eLife Biosensors Alzheimer's disease microtubules tau seeding Nanoluciferase |
| title | Novel repertoire of tau biosensors to monitor pathological tau transformation and seeding activity in living cells |
| title_full | Novel repertoire of tau biosensors to monitor pathological tau transformation and seeding activity in living cells |
| title_fullStr | Novel repertoire of tau biosensors to monitor pathological tau transformation and seeding activity in living cells |
| title_full_unstemmed | Novel repertoire of tau biosensors to monitor pathological tau transformation and seeding activity in living cells |
| title_short | Novel repertoire of tau biosensors to monitor pathological tau transformation and seeding activity in living cells |
| title_sort | novel repertoire of tau biosensors to monitor pathological tau transformation and seeding activity in living cells |
| topic | Biosensors Alzheimer's disease microtubules tau seeding Nanoluciferase |
| url | https://elifesciences.org/articles/78360 |
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