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

Author

Listed:
  • Benjamin Caballero

    (Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Roche Chile Pharmaceuticals)

  • Mathieu Bourdenx

    (Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Institut des Maladies Neurodégénératives, CNRS, Université de Bordeaux)

  • Enrique Luengo

    (Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Universidad Autonoma de Madrid
    Instituto de Investigación Biosanitaria Hospital de la Princesa)

  • Antonio Diaz

    (Albert Einstein College of Medicine
    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
    Albert Einstein College of Medicine)

  • Susanne Wegmann

    (Harvard Medical School
    German Center for Neurodegenerative Diseases (DZNE))

  • Bindi Patel

    (Albert Einstein College of Medicine
    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
    Albert Einstein College of Medicine
    Instituto Ramón y Cajal de Investigaciones Sanitarias Hospital Ramón y Cajal)

  • Hao Shao

    (University of California at San Francisco)

  • Manuela G. Lopez

    (Universidad Autonoma de Madrid
    Instituto de Investigación Biosanitaria Hospital de la Princesa)

  • 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
    Albert Einstein College of Medicine)

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.

Suggested Citation

  • 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, 2021. "Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22501-9
    DOI: 10.1038/s41467-021-22501-9
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    Cited by:

    1. Xiaoyan Xu & Tingxue Xie & Mengxin Zhou & Yaqin Sun & Fengqi Wang & Yanan Tian & Ziyan Chen & Yanqi Xie & Ronghai Wu & Xufeng Cen & Jichun Zhou & Tingjun Hou & Lei Zhang & Chaoyang Huang & Qingwei Zha, 2024. "Hsc70 promotes anti-tumor immunity by targeting PD-L1 for lysosomal degradation," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Chao Wang & Li Fan & Rabia R. Khawaja & Bangyan Liu & Lihong Zhan & Lay Kodama & Marcus Chin & Yaqiao Li & David Le & Yungui Zhou & Carlo Condello & Lea T. Grinberg & William W. Seeley & Bruce L. Mill, 2022. "Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. Pijush Chakraborty & Gwladys Rivière & Alina Hebestreit & Alain Ibáñez Opakua & Ina M. Vorberg & Loren B. Andreas & Markus Zweckstetter, 2023. "Acetylation discriminates disease-specific tau deposition," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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