Roskamp Institute, Sarasota, Florida 34243; The Open University, Milton Keynes MK7 6AA, United Kingdom; James A. Haley Veterans Hospital, Tampa, Florida 33612.
Roskamp Institute, Sarasota, Florida 34243; James A. Haley Veterans Hospital, Tampa, Florida 33612.
J Biol Chem. 2019 Sep 6;294(36):13378-13395. doi: 10.1074/jbc.RA119.008033. Epub 2019 Jul 19.
Spleen tyrosine kinase (SYK) plays a major role in inflammation and in adaptive immune responses and could therefore contribute to the neuroinflammation observed in various neurodegenerative diseases. Indeed, previously we have reported that SYK also regulates β-amyloid (Aβ) production and hyperphosphorylation of Tau protein involved in these diseases. Moreover, SYK hyperactivation occurs in a subset of activated microglia, in dystrophic neurites surrounding Aβ deposits, and in neurons affected by Tau pathology both in individuals with Alzheimer's disease (AD) and in AD mouse models. SYK activation increases Tau phosphorylation and accumulation, suggesting that SYK could be an attractive target for treating AD. However, the mechanism by which SYK affects Tau pathology is not clear. In this study, using cell biology and biochemical approaches, along with immunoprecipitation and immunoblotting, quantitative RT-PCR, and ELISAs, we found that SYK inhibition increases autophagic Tau degradation without impacting Tau production. Using neuron-like SH-SY5Y cells, we demonstrate that SYK acts upstream of the mammalian target of rapamycin (mTOR) pathway and that pharmacological inhibition or knockdown of SYK decreases mTOR pathway activation and increases autophagic Tau degradation. Interestingly, chronic SYK inhibition in a tauopathy mouse model profoundly reduced Tau accumulation, neuroinflammation, neuronal and synaptic loss, and also reversed defective autophagy. Our results further suggest that the SYK up-regulation observed in the brains of individuals with AD contributes to defective autophagic clearance leading to the accumulation of pathogenic Tau species. These findings further highlight SYK as a therapeutic target for the treatment of tauopathies and other neurodegenerative proteinopathies associated with defective autophagic clearance.
脾酪氨酸激酶（SYK）在炎症和适应性免疫反应中发挥主要作用，因此可能导致各种神经退行性疾病中观察到的神经炎症。事实上，我们之前曾报道过，SYK 还调节β-淀粉样蛋白（Aβ）的产生和与这些疾病相关的 Tau 蛋白的过度磷酸化。此外，SYK 的过度激活发生在一小部分活化的小胶质细胞中、在围绕 Aβ 沉积的变性神经突中、以及在受 Tau 病理学影响的神经元中，这些神经元存在于阿尔茨海默病（AD）患者和 AD 小鼠模型中。SYK 的激活增加了 Tau 的磷酸化和积累，这表明 SYK 可能是治疗 AD 的一个有吸引力的靶点。然而，SYK 影响 Tau 病理学的机制尚不清楚。在这项研究中，我们使用细胞生物学和生化方法，以及免疫沉淀和免疫印迹、定量 RT-PCR 和 ELISA，发现 SYK 抑制增加了自噬 Tau 的降解，而不影响 Tau 的产生。我们使用类神经元 SH-SY5Y 细胞证明，SYK 作用于雷帕霉素靶蛋白（mTOR）途径的上游，并且 SYK 的药理学抑制或敲低降低了 mTOR 途径的激活并增加了自噬 Tau 的降解。有趣的是，在 tau 病小鼠模型中慢性 SYK 抑制可显著减少 Tau 积累、神经炎症、神经元和突触损失，并且还逆转了缺陷型自噬。我们的研究结果进一步表明，AD 患者大脑中观察到的 SYK 上调导致了缺陷型自噬清除，从而导致致病性 Tau 物种的积累。这些发现进一步强调了 SYK 作为治疗 tau 病和其他与缺陷型自噬清除相关的神经退行性蛋白病的治疗靶点的重要性。
