Dual truncation of tau by caspase-2 accelerates its CHIP-mediated degradation.

Autor: Reinhardt L; BioMed X Institute, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany; AbbVie Deutschland GmbH & Co. KG, Neuroscience Discovery, Knollstrasse, 67061 Ludwigshafen am Rhein, Germany., Musacchio F; Neuroimmunology and Imaging Group, German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, Building 99, 53127 Bonn, Germany., Bichmann M; BioMed X Institute, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany., Behrendt A; BioMed X Institute, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany., Ercan-Herbst E; BioMed X Institute, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany., Stein J; AbbVie Deutschland GmbH & Co. KG, Neuroscience Discovery, Knollstrasse, 67061 Ludwigshafen am Rhein, Germany., Becher I; European Molecular Biology Laboratory (EMBL), Meyerhofstraße 1, 69117 Heidelberg, Germany., Haberkant P; European Molecular Biology Laboratory (EMBL), Meyerhofstraße 1, 69117 Heidelberg, Germany., Mader J; AbbVie Deutschland GmbH & Co. KG, Neuroscience Discovery, Knollstrasse, 67061 Ludwigshafen am Rhein, Germany., Schöndorf DC; BioMed X Institute, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany; AbbVie Deutschland GmbH & Co. KG, Neuroscience Discovery, Knollstrasse, 67061 Ludwigshafen am Rhein, Germany., Schmitt M; AbbVie Deutschland GmbH & Co. KG, Neuroscience Discovery, Knollstrasse, 67061 Ludwigshafen am Rhein, Germany., Korffmann J; AbbVie Deutschland GmbH & Co. KG, Neuroscience Discovery, Knollstrasse, 67061 Ludwigshafen am Rhein, Germany., Reinhardt P; AbbVie Deutschland GmbH & Co. KG, Neuroscience Discovery, Knollstrasse, 67061 Ludwigshafen am Rhein, Germany., Pohl C; AbbVie Deutschland GmbH & Co. KG, Neuroscience Discovery, Knollstrasse, 67061 Ludwigshafen am Rhein, Germany., Savitski M; European Molecular Biology Laboratory (EMBL), Meyerhofstraße 1, 69117 Heidelberg, Germany., Klein C; AbbVie Deutschland GmbH & Co. KG, Neuroscience Discovery, Knollstrasse, 67061 Ludwigshafen am Rhein, Germany., Gasparini L; AbbVie Deutschland GmbH & Co. KG, Neuroscience Discovery, Knollstrasse, 67061 Ludwigshafen am Rhein, Germany., Fuhrmann M; Neuroimmunology and Imaging Group, German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, Building 99, 53127 Bonn, Germany., Ehrnhoefer DE; BioMed X Institute, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany; AbbVie Deutschland GmbH & Co. KG, Neuroscience Discovery, Knollstrasse, 67061 Ludwigshafen am Rhein, Germany. Electronic address: dagmar.ehrnhoefer@abbvie.com.
Jazyk: angličtina
Zdroj: Neurobiology of disease [Neurobiol Dis] 2023 Jun 15; Vol. 182, pp. 106126. Date of Electronic Publication: 2023 Apr 20.
DOI: 10.1016/j.nbd.2023.106126
Abstrakt: Intraneuronal aggregates of the microtubule binding protein Tau are a hallmark of different neurodegenerative diseases including Alzheimer's disease (AD). In these aggregates, Tau is modified by posttranslational modifications such as phosphorylation as well as by proteolytic cleavage. Here we identify a novel Tau cleavage site at aspartate 65 (D65) that is specific for caspase-2. In addition, we show that the previously described cleavage site at D421 is also efficiently processed by caspase-2, and both sites are cleaved in human brain samples. Caspase-2-generated Tau fragments show increased aggregation potential in vitro, but do not accumulate in vivo after AAV-mediated overexpression in mouse hippocampus. Interestingly, we observe that steady-state protein levels of caspase-2 generated Tau fragments are low in our in vivo model despite strong RNA expression, suggesting efficient clearance. Consistent with this hypothesis, we find that caspase-2 cleavage significantly improves the recognition of Tau by the ubiquitin E3 ligase CHIP, leading to increased ubiquitination and faster degradation of Tau fragments. Taken together our data thus suggest that CHIP-induced ubiquitination is of particular importance for the clearance of caspase-2 generated Tau fragments in vitro and in vivo.
Competing Interests: Declaration of Competing Interest JM, MS, JK, PR, LG, CP and CK are employees of AbbVie, LR, DCS and DEE joined AbbVie as employees during the study. JS was an employee of AbbVie at the time of the study. FM and MF are employees of the German Center for Neurodegenerative Diseases (DZNE), their contributions to the study were funded by BioMed X GmbH. PH, MS and IB are employees of EMBL, their contributions to the study were funded by BioMed X GmbH. EEH is an employee of BioMed X GmbH, MB and AB were employees of BioMed X GmbH at the time of the study (a contract research agreement was funded by AbbVie). The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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