Academic Journal
Inhibition of DYRK1A proteolysis modifies its kinase specificity and rescues Alzheimer phenotype in APP/PS1 mice
| العنوان: | Inhibition of DYRK1A proteolysis modifies its kinase specificity and rescues Alzheimer phenotype in APP/PS1 mice |
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| المؤلفون: | Souchet, Benoit, Audrain, Mickael, Billard, Jean Marie, Dairou, Julien, Fol, Romain, Orefice, Nicola Salvatore, Tada, Satoru, Gu, Yuchen, Dufayet-Chaffaud, Gaelle, Limanton, Emmanuelle, Carreaux, François, Bazureau, Jean-Pierre, Alves, Sandro, Meijer, Laurent, Janel, Nathalie, Braudeau, Jérome, Cartier, Nathalie |
| المساهمون: | Thérapie génique, Génomique et Epigénomique (U 1169), Molecular Imaging Research Center Fontenay-aux-Roses (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Psychiatrie et Neurosciences (U894), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Mobilités : Vieillissement, Pathologie, Santé (COMETE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS), ManRos Therapeutics, ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011) |
| المصدر: | ISSN: 2051-5960 ; Acta Neuropathologica Communications ; https://normandie-univ.hal.science/hal-02324924 ; Acta Neuropathologica Communications, 2019, 7 (1), pp.46. ⟨10.1186/s40478-019-0678-6⟩. |
| بيانات النشر: | HAL CCSD BioMed Central part of Springer Science |
| سنة النشر: | 2019 |
| المجموعة: | Université de Rennes 1: Publications scientifiques (HAL) |
| مصطلحات موضوعية: | Kinase specificity, Therapeutic approach, Alzheimer's disease, DYRK1A, Proteolysis, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] |
| الوصف: | International audience ; Recent evidences suggest the involvement of DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1 A) in Alzheimer's disease (AD). Here we showed that DYRK1A undergoes a proteolytic processing in AD patients hippocampus without consequences on its kinase activity. Resulting truncated forms accumulate in astrocytes and exhibit increased affinity towards STAT3ɑ, a regulator of inflammatory process. These findings were confirmed in APP/ PS1 mice, an amyloid model of AD, suggesting that this DYRK1A cleavage is a consequence of the amyloid pathology. We identified in vitro the Leucettine L41 as a compound able to prevent DYRK1A proteolysis in both human and mouse protein extracts. We then showed that intraperitoneal injections of L41 in aged APP/PS1 mice inhibit STAT3ɑ phosphorylation and reduce pro-inflammatory cytokines levels (IL1-β, TNF-ɑ and IL-12) associated to an increased microglial recruitment around amyloid plaques and decreased amyloid-β plaque burden. Importantly, L41 treatment improved synaptic plasticity and rescued memory functions in APP/PS1 mice. Collectively, our results suggest that DYRK1A may contribute to AD pathology through its proteolytic process, reducing its kinase specificity. Further evaluation of inhibitors of DYRK1A truncation promises a new therapeutic approach for AD. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/30885273; hal-02324924; https://normandie-univ.hal.science/hal-02324924; https://normandie-univ.hal.science/hal-02324924/document; https://normandie-univ.hal.science/hal-02324924/file/INHIBITION%20OF%20dyrk1A.pdf; PUBMED: 30885273 |
| DOI: | 10.1186/s40478-019-0678-6 |
| الاتاحة: | https://normandie-univ.hal.science/hal-02324924 https://normandie-univ.hal.science/hal-02324924/document https://normandie-univ.hal.science/hal-02324924/file/INHIBITION%20OF%20dyrk1A.pdf https://doi.org/10.1186/s40478-019-0678-6 |
| Rights: | info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.4BCFC96F |
| قاعدة البيانات: | BASE |
| DOI: | 10.1186/s40478-019-0678-6 |
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