Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice

Benjamin Caballero, Mathieu Bourdenx, Enrique Luengo, Antonio Diaz, Peter Dongmin Sohn, Xu Chen, Chao Wang, Yves R. Juste, Susanne Wegmann, Bindi Patel, Zapporah T. Young, Szu Yu Kuo, Jose Antonio Rodriguez-Navarro, Hao Shao, Manuela G. Lopez, Celeste M. Karch, Alison M. Goate, Jason E. Gestwicki, Bradley T. Hyman, Li Gan and Ana Maria Cuervo ()
Additional contact information
Benjamin Caballero: Albert Einstein College of Medicine
Mathieu Bourdenx: Albert Einstein College of Medicine
Enrique Luengo: Albert Einstein College of Medicine
Antonio Diaz: Albert Einstein College of Medicine
Peter Dongmin Sohn: Weill Cornell Medicine
Xu Chen: Weill Cornell Medicine
Chao Wang: Weill Cornell Medicine
Yves R. Juste: Albert Einstein College of Medicine
Susanne Wegmann: Harvard Medical School
Bindi Patel: Albert Einstein College of Medicine
Zapporah T. Young: University of California at San Francisco
Szu Yu Kuo: University of California at San Francisco
Jose Antonio Rodriguez-Navarro: Albert Einstein College of Medicine
Hao Shao: University of California at San Francisco
Manuela G. Lopez: Universidad Autonoma de Madrid
Celeste M. Karch: Washington University
Alison M. Goate: Icahn School of Medicine at Mount Sinai
Jason E. Gestwicki: University of California at San Francisco
Bradley T. Hyman: Harvard Medical School
Li Gan: Weill Cornell Medicine
Ana Maria Cuervo: Albert Einstein College of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract Disrupted homeostasis of the microtubule binding protein tau is a shared feature of a set of neurodegenerative disorders known as tauopathies. Acetylation of soluble tau is an early pathological event in neurodegeneration. In this work, we find that a large fraction of neuronal tau is degraded by chaperone-mediated autophagy (CMA) whereas, upon acetylation, tau is preferentially degraded by macroautophagy and endosomal microautophagy. Rerouting of acetylated tau to these other autophagic pathways originates, in part, from the inhibitory effect that acetylated tau exerts on CMA and results in its extracellular release. In fact, experimental blockage of CMA enhances cell-to-cell propagation of pathogenic tau in a mouse model of tauopathy. Furthermore, analysis of lysosomes isolated from brains of patients with tauopathies demonstrates similar molecular mechanisms leading to CMA dysfunction. This study reveals that CMA failure in tauopathy brains alters tau homeostasis and could contribute to aggravate disease progression.

Date: 2021
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DOI: 10.1038/s41467-021-22501-9

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