Gladstone Institute of Neurological Disease, University of California, San Francisco, CA, 94158, USA.
Department of Neurology, University of California, San Francisco, CA, 94158, USA.
Mol Neurodegener. 2020 Jan 6;15(1):2. doi: 10.1186/s13024-019-0354-0.
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.
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.
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.
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.
tau 的跨神经元传播被认为与 tau 介导的神经退行性变的进展有关。目前，人们对 tau 的释放和传播方式以及疾病中这种方式如何失调知之甚少。先前，我们报道赖氨酸乙酰转移酶 p300/CBP 可以乙酰化 tau，调节其降解和毒性。然而，p300/CBP 是否参与调节 tau 的分泌和传播尚不清楚。
我们研究了 p300/CBP 活性、自噬溶酶体途径（ALP）与tau 分泌之间的关系，使用 tau 病的小鼠模型和培养的啮齿动物和人类神经元进行研究。通过高通量化合物筛选，我们鉴定出一种新的 p300 抑制剂，它可以促进自噬通量并减少 tau 的分泌。我们使用体外和体内纤维诱导 tau 扩散模型，研究了 p300/CBP 如何调节 tau 的传播。
tau 转基因小鼠模型中 p300/CBP 活性增加与 ALP 标志物异常积累有关。p300/CBP 过度激活会阻断神经元中的自噬通量并增加 tau 的分泌。相反，抑制 p300/CBP 可促进自噬通量，减少 tau 分泌，并减少体外和体内纤维诱导 tau 扩散模型中的 tau 传播。
我们报告说，在 tau 病中异常激活的赖氨酸乙酰转移酶 p300/CBP 会导致 ALP 受损，从而导致 tau 过度分泌。这种作用，加上细胞内 tau 积累增加，有助于增强 tau 的传播。我们的研究结果表明，抑制 p300/CBP 可能是一种纠正 tau 病中 ALP 功能障碍并阻止疾病进展的新方法。
