RT Journal Article
SR Electronic
T1 Tau Secretion and Propagation Is Regulated by p300/CBP via Autophagy-Lysosomal Pathway in Tauopathy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 418640
DO 10.1101/418640
A1 Xu Chen
A1 Yaqiao Li
A1 Chao Wang
A1 Yinyan Tang
A1 Sue-Ann Mok
A1 Richard M. Tsai
A1 Julio C. Rojas
A1 Anna Karydas
A1 Bruce L. Miller
A1 Adam L. Boxer
A1 Jason E. Gestwicki
A1 Ana Maria Cuervo
A1 Michelle Arkin
A1 Li Gan
YR 2018
UL http://biorxiv.org/content/early/2018/09/14/418640.abstract
AB 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.