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Tau Secretion and Propagation Is Regulated by p300/CBP via Autophagy-Lysosomal Pathway in Tauopathy

By Xu Chen, Yaqiao Li, Chao Wang, Yinyan Tang, Sue-Ann Mok, Richard M Tsai, Julio C Rojas, Anna Karydas, Bruce L. Miller, Adam L. Boxer, Jason E. Gestwicki, Ana Maria Cuervo, Michelle Arkin, Li Gan

Posted 14 Sep 2018
bioRxiv DOI: 10.1101/418640 (published DOI: 10.1186/s13024-019-0354-0)

The trans-neuronal propagation of tau has been implicated in the progression of tau-mediated neurodegeneration. Tau secretion from neurons is the first step in tau transmission, but little is known about the cellular mechanism. Here, we report that p300/CBP, the lysine acetyltransferase that acetylates tau and regulates its homeostasis and toxicity, serves as a key regulator of tau secretion by inhibiting the autophagy-lysosomal pathway (ALP). Increased p300/CBP activity was associated with impaired function of this pathway in a tau transgenic mouse model. p300/CBP hyperactivation increased tau secretion by blocking autophagic flux. Conversely, inhibiting p300/CBP genetically or pharmacologically promoted autophagic flux, and reduced tau accumulation, tau secretion, and tau propagation in fibril-induced tau spreading models in vitro and in vivo. Our findings show that p300/CBP-induced impairment in the ALP underlies excessive unconventional secretion and pathogenic spread of tau.

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