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Promoting tau secretion and propagation by hyperactive p300/CBP via autophagy-lysosomal pathway in tauopathy

Chen, Xu, Li, Yaqiao, Wang, Chao, Tang, Yinyan, Mok, Sue-Ann, Tsai, Richard M., Rojas, Julio C., Karydas, Anna, Miller, Bruce L., Boxer, Adam L., Gestwicki, Jason E., Arkin, Michelle, Cuervo, Ana Maria, Gan, Li·2020·Molecular Neurodegeneration
DOI 10.1186/s13024-019-0354-0PMC PMC6945522

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Abstract

Background: The trans-neuronal propagation of tau has been implicated in the progression of tau-mediated neurodegeneration. There is critical knowledge gap in understanding how tau is released and transmitted, and how that is dysregulated in diseases. Previously, we reported that lysine acetyltransferase p300/CBP acetylates tau and regulates its degradation and toxicity. However, whether p300/CBP is involved in regulation of tau secretion and propagation is unknown. Method: We investigated the relationship between p300/CBP activity, the autophagy-lysosomal pathway (ALP) and tau secretion in mouse models of tauopathy and in cultured rodent and human neurons. Through a high-through-put compound screen, we identified a new p300 inhibitor that promotes autophagic flux and reduces tau secretion. Using fibril-induced tau spreading models in vitro and in vivo, we examined how p300/CBP regulates tau propagation. Results: Increased p300/CBP activity was associated with aberrant accumulation of ALP markers in a tau transgenic mouse model. p300/CBP hyperactivation blocked autophagic flux and increased tau secretion in neurons. Conversely, inhibiting p300/CBP promoted autophagic flux, reduced tau secretion, and reduced tau propagation in fibril-induced tau spreading models in vitro and in vivo. Conclusions: We report that p300/CBP, a lysine acetyltransferase aberrantly activated in tauopathies, causes impairment in ALP, leading to excess tau secretion. This effect, together with increased intracellular tau accumulation, contributes to enhanced spreading of tau. Our findings suggest that inhibition of p300/CBP as a novel approach to correct ALP dysfunction and block disease progression in tauopathy.

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Metadata

Authors
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., Arkin, M., Cuervo, A. M., & Gan, L.
ORCID
Gan, Li
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2020-01-06
Volume
15
Issue
1
ISSN
1750-1326
DOI
10.1186/s13024-019-0354-0
PMC
PMC6945522
Cited by
107
References
20
Language
en
Licence
Funders
  • National Institute on Aging (R01AG054214, K99 AG053439)
  • National Institute of Neurological Disorders and Stroke (U54NS100717, R01NS059690)

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