Department of Neuroscience, Laboratory for Dementia and Parkinsonism, Georgetown University Medical Center, 3970 Reservoir Rd, NW, TRB, Room WP26B, Washington, DC, 20057, USA.
J Mol Med (Berl). 2014 Apr;92(4):373-86. doi: 10.1007/s00109-013-1112-3. Epub 2013 Dec 13.
Alzheimer's disease (AD) is a neurodegenerative disorder associated with amyloid accumulation and autophagic changes. Parkin is an E3 ubiquitin ligase involved in proteasomal and autophagic clearance. We previously demonstrated decreased parkin solubility and interaction with the key autophagy enzyme beclin-1 in AD, but tyrosine kinase inhibition restored parkin-beclin-1 interaction. In the current studies, we determined the mechanisms of nilotinib-induced parkin-beclin-1 interaction, which leads to amyloid clearance. Nilotinib increased endogenous parkin levels and ubiquitination, which may enhance parkin recycling via the proteasome, leading to increased activity and interaction with beclin-1. Parkin solubility was decreased and autophagy was altered in amyloid expressing mice, suggesting that amyloid stress affects parkin stability, leading to failure of protein clearance via the lysosome. Isolation of autophagic vacuoles revealed amyloid and parkin accumulation in autophagic compartments but nilotinib decreased insoluble parkin levels and facilitated amyloid deposition into lysosomes in wild type, but not parkin(-/-) mice, further underscoring an essential role for endogenous parkin in amyloid clearance. These results suggest that nilotinib boosts the autophagic machinery, leading to increased level of endogenous parkin that undergoes ubiquitination and interacts with beclin-1 to facilitate amyloid clearance. These data suggest that nilotinib-mediated autophagic changes may trigger parkin response via increased protein levels, providing a therapeutic strategy to reduce Aβ and Tau in AD.
Parkin solubility (stability) is decreased in AD and APP transgenic mice. Nilotinib-induced autophagic changes increase endogenous parkin level. Increased parkin level leads to ubiquitination and proteasomal recycling. Re-cycling decreases insoluble parkin and increases parkin-beclin-1 interaction. Beclin-1-parkin interaction enhances amyloid clearance.
阿尔茨海默病（AD）是一种与淀粉样蛋白积累和自噬变化有关的神经退行性疾病。Parkin 是一种参与蛋白酶体和自噬清除的 E3 泛素连接酶。我们之前的研究表明，AD 中 Parkin 的可溶性降低，与关键自噬酶 Beclin-1 的相互作用减弱，但酪氨酸激酶抑制可恢复 Parkin-Beclin-1 的相互作用。在当前的研究中，我们确定了尼洛替尼诱导 Parkin-Beclin-1 相互作用的机制，该机制导致淀粉样蛋白清除。尼洛替尼增加内源性 Parkin 水平和泛素化，这可能通过蛋白酶体增强 Parkin 的回收，从而增加与 Beclin-1 的活性和相互作用。在表达淀粉样蛋白的小鼠中，Parkin 的可溶性降低，自噬改变，表明淀粉样蛋白应激会影响 Parkin 的稳定性，导致通过溶酶体进行蛋白质清除失败。自噬小体的分离显示淀粉样蛋白和 Parkin 在自噬隔室中的积累，但尼洛替尼降低了野生型小鼠而不是 Parkin(-/-)小鼠中不可溶性 Parkin 的水平，并促进了淀粉样蛋白沉积到溶酶体中，进一步强调了内源性 Parkin 在淀粉样蛋白清除中的重要作用。这些结果表明，尼洛替尼增强了自噬机制，导致内源性 Parkin 水平升高，Parkin 经历泛素化并与 Beclin-1 相互作用，从而促进淀粉样蛋白清除。这些数据表明，尼洛替尼介导的自噬变化可能通过增加蛋白质水平触发 Parkin 反应，为减少 AD 中的 Aβ和 Tau 提供了一种治疗策略。
AD 和 APP 转基因小鼠中的 Parkin 可溶性（稳定性）降低。尼洛替尼诱导的自噬变化增加内源性 Parkin 水平。内源性 Parkin 水平的增加导致泛素化和蛋白酶体回收。回收减少不可溶性 Parkin 并增加 Parkin-Beclin-1 相互作用。Parkin-Beclin-1 相互作用增强淀粉样蛋白清除。
