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

Chen, X.; Li, Y.; Wang, C.; Tang, Y.; Mok, S.-A.; Tsai, R. M.; Rojas, J. C.; Karydas, A.; Miller, B. L.; Boxer, A. L.; Gestwicki, J. E.; Cuervo, A. M.; Arkin, M.; Gan, L.

doi:10.1101/418640

bioRxiv · 10.1101/418640

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

Chen, X.·Li, Y.·Wang, C.·Tang, Y.·Mok, S.-A.·Tsai, R. M.·Rojas, J. C.·Karydas, A.·Miller, B. L.·Boxer, A. L.·Gestwicki, J. E.·Cuervo, A. M.·Arkin, M.·Gan, L.

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Abstract

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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Chen, X., Li, Y., Wang, C., Tang, Y., Mok, S.-A., Tsai, R. M., Rojas, J. C., Karydas, A., Miller, B. L., Boxer, A. L., Gestwicki, J. E., Cuervo, A. M., Arkin, M., Gan, L.. 2018-09-14. Tau Secretion and Propagation Is Regulated by p300/CBP via Autophagy-Lysosomal Pathway in Tauopathy. https://doi.org/10.1101/418640

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