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

TitleAcetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice.
Publication TypeJournal Article
Year of Publication2021
AuthorsCaballero B, Bourdenx M, Luengo E, Diaz A, Sohn PDongmin, Chen X, Wang C, Juste YR, Wegmann S, Patel B, Young ZT, Kuo SYu, Rodriguez-Navarro JAntonio, Shao H, Lopez MG, Karch CM, Goate AM, Gestwicki JE, Hyman BT, Gan L, Cuervo AMaria
JournalNat Commun
Date Published2021 04 14

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.

Alternate JournalNat Commun
PubMed ID33854069
PubMed Central IDPMC8047017
Grant ListT32 GM007491 / GM / NIGMS NIH HHS / United States