Journal Article

DZNE-2023-00575

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Dual truncation of tau by caspase-2 accelerates its CHIP-mediated degradation.

Reinhardt, L. ; Musacchio, F.DZNE* ; Bichmann, M. ; Behrendt, A. ; Ercan-Herbst, E. ; Stein, J. ; Becher, I. ; Haberkant, P. ; Mader, J. ; Schöndorf, D. C. ; Schmitt, M. ; Korffmann, J. ; Reinhardt, P. ; Pohl, C. ; Savitski, M. ; Klein, C. ; Gasparini, L. ; Fuhrmann, M.DZNE* ; Ehrnhoefer, D. E.

2023
Elsevier [Amsterdam]

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Please use a persistent id in citations: doi:10.1016/j.nbd.2023.106126

Abstract: 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.

Keyword(s): Humans (MeSH) ; Male (MeSH) ; Female (MeSH) ; Animals (MeSH) ; Mice (MeSH) ; Disease Models, Animal (MeSH) ; tau Proteins: chemistry (MeSH) ; tau Proteins: genetics (MeSH) ; tau Proteins: metabolism (MeSH) ; Caspase 2: metabolism (MeSH) ; Brain: metabolism (MeSH) ; Chromatin Immunoprecipitation (MeSH) ; Ubiquitination (MeSH) ; CHIP ; Caspase-2 ; Degradation ; Proteolysis ; Tau ; Tauopathy ; Ubiquitination ; Mapt protein, mouse ; tau Proteins ; Caspase 2 ; CASP2 protein, human ; MAPT protein, human

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Contributing Institute(s):

1. Neuroimmunology and Imaging (AG Fuhrmann)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2023

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