Proteasome inhibition induces stress kinase dependent transport deficits - Implications for Alzheimer's disease
Proteasome inhibition induces stress kinase dependent transport deficits - Implications for Alzheimer's disease
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DOI：
10.1016/j.mcn.2013.11.001
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发表时间：
2014-01-01
影响因子：
3.5
通讯作者：
Hallbeck, Martin
中科院分区：
文献类型：
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作者：
Agholme, Lotta;Nath, Sangeeta;Hallbeck, Martin
阿尔茨海默病（AD）的特征在于两种错误折叠和聚集的蛋白质β-淀粉样蛋白和过度磷酸化的tau的积累。负责清除错误折叠和聚集的蛋白质的两种细胞系统，溶酶体和蛋白酶体，已被证明在老年大脑中发生故障，在神经退行性疾病（包括AD）患者中更是如此。这种功能障碍可能会导致β-淀粉样蛋白和tau蛋白的积累，最终聚集在瘟疫和缠结中。我们研究了蛋白酶体活性降低对tau蛋白磷酸化以及微管稳定性和转运的影响。为此，我们使用我们最近开发的神经元模型，其中人SH-SY 5 Y细胞通过分化获得神经元形态和功能。我们发现，暴露于低剂量的蛋白酶体抑制剂MG-115导致tau蛋白磷酸化，微管不稳定和神经炎运输紊乱。此外，降低的蛋白酶体活性激活了与tau磷酸化和AD病理学有关的几种蛋白，包括c-Jun N-末端激酶、c-Jun和细胞外信号调节蛋白激酶（ERK）1/2。通过抑制ERK 1/2活化实现微管转运的恢复，并且同时抑制ERK 1/2和c-Jun逆转了蛋白酶体抑制诱导的tau磷酸化。总之，这项研究表明，蛋白酶体活性的降低可以通过激活c-Jun和ERK 1/2，导致与神经退行性疾病相关的几个事件。蛋白酶体活性的恢复或ERK 1/2和c-Jun功能的调节可以为神经退行性疾病如AD开辟新的治疗可能性。(C)2013 Elsevier Inc. All rights reserved.
Alzheimer's disease (AD) is characterized by accumulation of two misfolded and aggregated proteins, beta-amyloid and hyperphosphorylated tau. Both cellular systems responsible for clearance of misfolded and aggregated proteins, the lysosomal and the proteasomal, have been shown to be malfunctioning in the aged brain and more so in patients with neurodegenerative diseases, including AD. This malfunction could be contributing to beta-amyloid and tau accumulation, eventually aggregating in plagues and tangles. We have investigated the impact of decreased proteasome activity on tau phosphorylation as well as on microtubule stability and transport. To do this, we used our recently developed neuronal model where human SH-SY5Y cells obtain neuronal morphology and function through differentiation. We found that exposure to low doses of the proteasome inhibitor MG-115 caused tau phosphorylation, microtubule destabilization and disturbed neuritic transport. Furthermore, reduced proteasome activity activated several proteins implicated in tau phosphorylation and AD pathology, including c-Jun N-terminal kinase, c-Jun and extracellular signal-regulated protein kinase (ERK) 1/2. Restoration of the microtubule transport was achieved by inhibiting ERK 1/2 activation, and simultaneous inhibition of both ERK 1/2 and c-Jun reversed the proteasome inhibition-induced tau phosphorylation. Taken together, this study suggests that a decrease in proteasome activity can, through activation of c-Jun and ERK 1/2, result in several events related to neurodegenerative diseases. Restoration of proteasome activity or modulation of ERK 1/2 and c-Jun function can open new treatment possibilities against neurodegenerative diseases such as AD. (C) 2013 Elsevier Inc. All rights reserved.