Inhibition of DYRK1A proteolysis modifies its kinase specificity and rescues Alzheimer phenotype in APP/PS1 mice

Benoit Souchet; Mickael Audrain; Jean Marie Billard; Julien Dairou; Romain Fol; Nicola Salvatore Orefice; Satoru Tada; Yuchen Gu; Gaelle Dufayet-Chaffaud; Emmanuelle Limanton; François Carreaux; Jean-Pierre Bazureau; Sandro Alves; Laurent Meijer; Nathalie Janel; Jérome Braudeau; Nathalie Cartier

doi:10.1186/s40478-019-0678-6

Journal articles

Inhibition of DYRK1A proteolysis modifies its kinase specificity and rescues Alzheimer phenotype in APP/PS1 mice

Benoit Souchet ^{1, 2, *} Mickael Audrain ¹ Jean Marie Billard ^{3, 4} Julien Dairou ⁵ Romain Fol ¹ Nicola Salvatore Orefice ¹ Satoru Tada ¹ Yuchen Gu ^{3, 2} Gaelle Dufayet-Chaffaud ¹ Emmanuelle Limanton ⁶ François Carreaux ⁶ Jean-Pierre Bazureau ⁶ Sandro Alves ¹ Laurent Meijer ⁷ Nathalie Janel ² Jérome Braudeau ^{1, *} Nathalie Cartier ^{1, *}

* Corresponding author

1 U 1169 - Thérapie génique, Génomique et Epigénomique

2 BFA (UMR_8251 / U1133) - Unité de Biologie Fonctionnelle et Adaptative

3 U894 / UMS 1266 - Institut de psychiatrie et neurosciences

4 COMETE - Mobilités : Vieillissement, Pathologie, Santé

5 LCBPT - UMR 8601 - Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques

6 ISCR - Institut des Sciences Chimiques de Rennes

7 ManRos Therapeutics

Abstract : 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.

Keywords : Kinase specificity Proteolysis DYRK1A Therapeutic approach Alzheimer's disease

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Journal articles

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Life Sciences [q-bio] / Neurons and Cognition [q-bio.NC]

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Inhibition of DYRK1A proteolysis modifies its kinase specificity and rescues Alzheimer phenotype in APP/PS1 mice

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