Motifs in the tau protein that control binding to microtubules and aggregation determine pathological effects
| العنوان: | Motifs in the tau protein that control binding to microtubules and aggregation determine pathological effects |
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| المؤلفون: | Paolo Paganetti, Pamela Valdés, Graham Knott, Bernard L. Schneider, Matthias Cacquevel, Catherine Maclachlan, Aurélien Lathuilière, Stéphanie Papin, Andreas Muhs |
| المصدر: | Scientific Reports Scientific Reports, Vol 7, Iss 1, Pp 1-18 (2017) Scientific reports, Vol. 7, No 1 (2017) P. 13556 |
| بيانات النشر: | Springer Science and Business Media LLC, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, lcsh:Medicine, medicine.disease_cause, Microtubules, Mice, 0302 clinical medicine, Phosphorylation, Cognitive decline, lcsh:Science, Cytoskeleton, Cerebral Cortex, Neurons, Tau Proteins / genetics, Mutation, Multidisciplinary, biology, Chemistry, Neurons / metabolism, Prosencephalon / pathology, Cell biology, Cerebral Cortex / pathology, Protein Binding, Frontotemporal dementia, Microtubules / metabolism, Genetic Vectors, Tau protein, Prosencephalon / metabolism, Hyperphosphorylation, tau Proteins, Article, 03 medical and health sciences, Prosencephalon, Alzheimer Disease, Microtubule, mental disorders, Genetic Vectors / metabolism, medicine, Animals, Humans, Alzheimer Disease / pathology, lcsh:R, medicine.disease, Alzheimer Disease / metabolism, Mice, Inbred C57BL, 030104 developmental biology, Animals, Newborn, Cerebral Cortex / ultrastructure, Rotarod Performance Test, Mutagenesis, Site-Directed, biology.protein, lcsh:Q, Protein Conformation, beta-Strand, Tau Proteins / metabolism, 030217 neurology & neurosurgery |
| الوصف: | Tau pathology is associated with cognitive decline in Alzheimer’s disease, and missense tau mutations cause frontotemporal dementia. Hyperphosphorylation and misfolding of tau are considered critical steps leading to tauopathies. Here, we determine how motifs controlling conformational changes in the microtubule-binding domain determine tau pathology in vivo. Human tau was overexpressed in the adult mouse forebrain to compare variants carrying residues that modulate tau propensity to acquire a β-sheet conformation. The P301S mutation linked to frontotemporal dementia causes tau aggregation and rapidly progressing motor deficits. By comparison, wild-type tau becomes heavily hyperphosphorylated, and induces behavioral impairments that do not progress over time. However, the behavioral defects caused by wild-type tau can be suppressed when β-sheet breaking proline residues are introduced in the microtubule-binding domain of tau. This modification facilitates tau interaction with microtubules, as shown by lower levels of phosphorylation, and by the enhanced protective effects of mutated tau against the severing of the cytoskeleton in neurons exposed to vinblastine. Altogether, motifs that are critical for tau conformation determine interaction with microtubules and subsequent pathological modifications, including phosphorylation and aggregation. |
| تدمد: | 2045-2322 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cf4a61a4863f9e037384c818204e8fafTest https://doi.org/10.1038/s41598-017-13786-2Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....cf4a61a4863f9e037384c818204e8faf |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20452322 |
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