Transfer of α-synuclein from neurons to oligodendrocytes triggers myelin sheath destruction in methamphetamine administration mice
Transfer of α-synuclein from neurons to oligodendrocytes triggers myelin sheath destruction in methamphetamine administration mice
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DOI：
10.1016/j.toxlet.2021.09.005
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发表时间：
2021-10-06
影响因子：
3.5
通讯作者：
Wang, Yuanhe
中科院分区：
文献类型：
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作者：
Ding, Jiuyang;Huang, Jian;Wang, Yuanhe
甲基苯丙胺(METH)是一种广泛滥用的神经系统兴奋剂，可通过α-突触核蛋白(α-SYN)引起神经毒性。在冰毒小鼠模型中，少突胶质细胞的病理基础是神经源性的α-突触传递，目前对此知之甚少。在这项研究中，我们测试了慢性冰毒小鼠模型中的α-syn水平、少突胶质细胞病理学和自噬溶酶体途径(ALP)的功能。METH使神经元中α-突触蛋白水平升高，然后在少突胶质细胞中蓄积。METH增加磷酸化mTOR水平，降低转录因子EB(TFEB)水平，触发自噬溶酶体途径(ALP)损伤，导致髓鞘破坏、少突胶质蛋白丢失、成熟树突棘丢失、神经元丢失和星形胶质细胞激活。去除内源性α-syn可提高TFEB水平，减轻ALP缺失，减轻冰毒所致的神经病理改变。TFEB在少突胶质细胞中的过表达对甲基苯丙胺小鼠模型有一定的保护作用。这些神经保护作用与少突胶质细胞TFEB过表达后挽救的ALP机制有关。我们的研究首次证明，α-SYN-TFEB轴可能参与冰毒诱导的髓鞘丢失、少突胶质细胞病理和神经病理。总而言之，靶向α-SYN-TFEB轴可能是治疗冰毒诱导的少突胶质细胞病理以及更广泛的视野下神经退行性疾病的一种有前途的治疗策略。(C)2021年爱思唯尔B.V.保留所有权利。
Methamphetamine (METH), a widely abused nervous system stimulant, could induce neurotoxicity through alpha-synuclein (alpha-syn). Not much is known about the neuronal derived alpha-syn transmission that underlies oligodendrocyte pathology in METH mice model. In this study, we tested alpha-syn level, oligodendroglial pathology and autophagy lysosome pathway (ALP) function in corpus callosum in a chronic METH mice model. METH increased alpha-syn level in neurons and then accumulated in oligodendrocytes. METH increased phosphor-mTOR level, decreased transcription factor EB (TFEB) level and triggered autophagy lysosomal pathway (ALP) impairment, leading to myelin sheath destruction, oligodendroglial proteins loss, mature dendritic spine loss, neuron loss, and astrocyte activation. Deleting endogenous alpha-syn increased TFEB level, alleviated ALP deficit, and diminished neuropathology induced by METH. TFEB overexpression in oligodendrocytes exerted beneficial effects in METH mice model. These neuroprotective effects were associated with the rescued ALP machinery after oligodendroglial TFEB overexpression. Our study demonstrated, for the first time, that alpha-syn-TFEB axis might be involve in the METH induced myelin loss, oligodendroglial pathology, and neuropathology. In summary, targeting at the alpha-syn-TFEB axis might be a promising therapeutic strategy for treating METH induced oligodendroglial pathology, and to a broader view, neurodegenerative diseases. (C) 2021 Elsevier B.V. All rights reserved.