Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of -synuclein in Parkinsons disease models
Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of -synuclein in Parkinsons disease models
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DOI：
10.1093/hmg/ddt192
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发表时间：
2013-08-15
影响因子：
3.5
通讯作者：
Moussa, Charbel E-H
中科院分区：
文献类型：
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作者：
Hebron, Michaeline L.;Lonskaya, Irina;Moussa, Charbel E-H
帕金森病是一种运动障碍性疾病，其特征是黑质多巴胺能神经元死亡和脑内β-突触核蛋白积聚。酪氨酸激酶Abl在神经变性中被激活。在这里，我们表明，慢病毒表达的-突触核蛋白在小鼠SN中导致Abl激活（磷酸化）和慢病毒Abl表达增加-突触核蛋白水平，与Abl激活PD大脑。在转基因和慢病毒基因转移模型中，给予酪氨酸激酶抑制剂尼洛替尼可降低Abl活性并改善自噬清除-突触核蛋白。亚细胞分级显示-突触核蛋白和过度磷酸化的Tau（p-Tau）在表达-突触核蛋白的大脑中的自噬空泡中积累，但尼洛替尼增强了蛋白质沉积到溶酶体中。尼洛替尼用于成人白血病治疗，其在美国食品药品监督管理局批准的剂量范围内进入大脑，导致β-突触核蛋白的自噬降解，保护SN神经元并改善运动表现。这些数据表明，尼洛替尼可能是一种治疗策略，以降解β-突触核蛋白在PD和其他β-突触核蛋白病。
Parkinsons disease is a movement disorder characterized by death of dopaminergic substantia nigra (SN) neurons and brain accumulation of -synuclein. The tyrosine kinase Abl is activated in neurodegeneration. Here, we show that lentiviral expression of -synuclein in the mouse SN leads to Abl activation (phosphorylation) and lentiviral Abl expression increases -synuclein levels, in agreement with Abl activation in PD brains. Administration of the tyrosine kinase inhibitor nilotinib decreases Abl activity and ameliorates autophagic clearance of -synuclein in transgenic and lentiviral gene transfer models. Subcellular fractionation shows accumulation of -synuclein and hyper-phosphorylated Tau (p-Tau) in autophagic vacuoles in -synuclein expressing brains, but nilotinib enhances protein deposition into the lysosomes. Nilotinib is used for adult leukemia treatment and it enters the brain within US Food and Drug Administration approved doses, leading to autophagic degradation of -synuclein, protection of SN neurons and amelioration of motor performance. These data suggest that nilotinib may be a therapeutic strategy to degrade -synuclein in PD and other -synucleinopathies.