Alpha-Synuclein deficiency ameliorates chronic methamphetamine induced neurodegeneration in mice
Alpha-Synuclein deficiency ameliorates chronic methamphetamine induced neurodegeneration in mice
复制标题
α-突触核蛋白缺乏可改善小鼠慢性甲基苯丙胺诱导的神经变性
DOI：
10.1016/j.tox.2020.152461
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发表时间：
2020-05-30
期刊：
影响因子：
4.5
通讯作者：
Qiu, Pingming
中科院分区：
文献类型：
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作者：
Ding, Jiuyang;Hu, Shanshan;Qiu, Pingming
α-突触核蛋白（alpha-syn）和tau对环境因素或基因突变诱导的神经退行性疾病具有协同作用。因此，我们研究了α-syn和tau在慢性甲基苯丙胺（METH）暴露（1.0类似于20.0 mg/kg/d体重，连续14天）诱导的神经变性中的作用。在这里，我们提出了一个小鼠模型，有证据表明α-syn和tau参与慢性METH的毒理学。METH使海马CA 1、CA 2、CA 3区的起始层、锥体层、放射层、分子层、齿状回多形层和黑质α-syn水平升高。上调的alpha-syn的亚细胞定位主要发现在线粒体和轴突。METH上调的α-syn可直接诱导线粒体损伤、髓鞘破坏和突触失效。此外，过量的a-syn可能通过tau激酶GSK 3 β和CDK 5间接促进tau磷酸化，导致微管解聚并最终导致自噬体和溶酶体融合缺陷。在体外实验中，自噬泡不能与溶酶体融合。alpha-syn基因敲除可减轻alpha-syn直接和间接作用引起的神经病理学改变。总之，这些结果表明，α-syn介导慢性METH诱导的神经退行性过程，减少α-syn可能是一种潜在的方法，以保护METH的毒性作用，也是，从更广泛的角度来看，在神经退行性疾病的治疗价值。
The alpha-Synuclein (alpha-syn) and tau have synergistic effects on neurodegenerative diseases induced by environmental factors or genetic mutation. Thus, we in-vestigated the role of alpha-syn and tau in neurodegeneration induced by chronic methamphetamine (METH) exposure (1.0 similar to 20.0 mg/kg/d body weight, for 14 consecutive days). Here, we present a mice model with evidences of alpha-syn and tau participating in toxicology in chronic METH. METH increased alpha-syn level in the stratum oriens, pyramidal layer, stratum radiatum and stratum moleculare of hippocampal CA1, CA2 and CA3, polymorph layer of hippocampal dentate gyrus (DG), and substantia nigra (SN). The subcellular locations of the upregulated alpha-syn were mainly found in mitochondria and axons. The METH upregulated alpha-syn may directly induce mitochondrial damage, myelin sheath destruction, and synaptic failure. Also, the excess a-syn might indirectly promote tau phosphorylation through tau kinase GSK3 beta and CDK5, leading to microtubule depolymerization and eventually fusion deficit of autophagosome and lysosome. In the in vitro experiment, the autophagic vacuoles failed to fuse with the lysosome. The neuropathology induced by both the direct and indirect effects of alpha-syn could be alleviated by alpha-syn knockout. Taking together, these results indicate that the alpha-syn mediates the neurodegenerative process induced by chronic METH and that reducing alpha-syn might be a potential approach to protect the toxic effects of METH and also be, to a broader view, of therapeutic value in neurodegenerative diseases.