2. Academic Validation
  3. Promoting tau secretion and propagation by hyperactive p300/CBP via autophagy-lysosomal pathway in tauopathy

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

  • Mol Neurodegener. 2020 Jan 6;15(1):2. doi: 10.1186/s13024-019-0354-0.
Xu Chen 1 2,  Yaqiao Li 3,  Chao Wang 3 4,  Yinyan Tang 5,  Sue-Ann Mok 6,  Richard M Tsai 4 7,  Julio C Rojas 4 7,  Anna Karydas 4 7,  Bruce L Miller 4 7,  Adam L Boxer 4 7,  Jason E Gestwicki 6,  Michelle Arkin 5,  Ana Maria Cuervo 8 9,  Li Gan 10 11 12
Affiliations

Affiliations

  • 1 Gladstone Institute of Neurological Disease, University of California, San Francisco, CA, 94158, USA. [email protected].
  • 2 Department of Neurology, University of California, San Francisco, CA, 94158, USA. [email protected].
  • 3 Gladstone Institute of Neurological Disease, University of California, San Francisco, CA, 94158, USA.
  • 4 Department of Neurology, University of California, San Francisco, CA, 94158, USA.
  • 5 Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, 94158, USA.
  • 6 Institute for Neurodegenerative Disease, Department of Pharmaceutical Chemistry, Weill Institute for Neurosciences, University of California, San Francisco, CA, 94158, USA.
  • 7 Memory and Aging Center, University of California, San Francisco, CA, 94158, USA.
  • 8 Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
  • 9 Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
  • 10 Gladstone Institute of Neurological Disease, University of California, San Francisco, CA, 94158, USA. [email protected].
  • 11 Department of Neurology, University of California, San Francisco, CA, 94158, USA. [email protected].
  • 12 Helen and Robert Appel Alzheimer's Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, 10065, USA. [email protected].
PMID: 31906970 DOI: 10.1186/s13024-019-0354-0
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.

Keywords

Autophagy-lysosomal pathway; Tau secretion; Tau spreading; Tauopathy; p300/CBP.

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