Description
Tau Secretion and Propagation Is Regulated by p300/CBP via Autophagy-Lysosomal Pathway
Xu Chen1,2,*, Yaqiao Li1, Chao Wang1,2, Yinyan Tang3, Sue-Ann Mok4, Richard M. Tsai2,5,
Julio C. Rojas2,5, Anna Karydas2,5, Bruce L. Miller2,5, Adam L. Boxer2,5, Jason E. Gestwicki4, Ana-Maria Cuervo6,7, Michelle Arkin3, and Li Gan1,2,*
1Gladstone Institute of Neurological Disease, 2Department of Neurology, 3Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, 4Institute for Neurodegenerative Disease, Department of Pharmaceutical Chemistry, Weill Institute for Neurosciences, 5Memory and Aging Center, University of California, San Francisco, CA 94158, USA, 6Department of Developmental and Molecular Biology, 7Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY 10461, USA
*Corresponding authors: lgan@gladstone.ucsf.edu, xu.chen@gladstone.ucsf.edu
The trans-neuronal propagation of tau has been implicated in the progression of tau-mediated neurodegeneration. Secretion of tau from neurons is the initial step towards tau transmission. However, little is known about the underlying cellular mechanism. Here, we report that p300/CBP - the lysine acetyltransferase that acetylates tau and regulates its homeostasis and toxicity - is a key regulator of tau secretion via modulating the autophagy-lysosomal pathway (ALP). We show that increased p300/CBP is associated with impaired ALP function in tau transgenic mouse model and in HEK293 reconstitution model. p300/CBP hyperactivation increases tau secretion via blockage of the autophagic flux. Conversely, inhibiting p300/CBP genetically or pharmacologically promotes autophagy, reduces tau accumulation and tau secretion, and ameliorates tau propagation in fibril-induced tau spreading models in vitro and in vivo. Our findings showed that p300/CBP-induced impairment in the ALP underlies excessive unconventional secretion and pathogenic spread of tau. The connections between p300, autophagy and tau secretion underscore the notion that aberrant metabolism might contribute to neurodegeneration.