Autophagy mediators (FOXO1, SESN3 and TSC2) in Lewy body disease and aging
Autophagy mediators (FOXO1, SESN3 and TSC2) in Lewy body disease and aging
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DOI：
10.1016/j.neulet.2018.06.052
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发表时间：
2018-09-25
影响因子：
2.5
通讯作者：
Wakabayashi, Koichi
中科院分区：
文献类型：
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作者：
Miki, Yasuo;Tanji, Kunikazu;Wakabayashi, Koichi
神经退行性疾病如帕金森病（PD）和路易体痴呆（DLB）的特征在于自噬受损。细胞存活依赖于磷酸化的α-突触核蛋白的有效清除，其作为纤维在神经元细胞质中积累为路易体（LB）。FOXO 1是FOXO家族的成员之一，在细胞内的各种过程中发挥作用，包括自噬的调节。据报道，FOXO 1的转录激活通过抑制由sestrin 3（SESN 3）和结节性硬化症复合体2（TSC 2）介导的雷帕霉素机制靶点（mTOR）的表达来启动自噬。虽然已知许多自噬相关蛋白被掺入LB中，但没有报告记录这些自噬调节剂（FOXO 1、SESN 3和TSC 2）参与PD和DLB的发病机制。在本研究中，我们使用正常对照和PD和DLB患者的大脑进行免疫染色和Western印迹分析，以阐明FOXO 1，SESN 3和TSC 2在LB中的参与。我们的研究首次证明了FOXO 1，SESN 3和TSC 2在脑干型LB中的存在。这些蛋白质在脑中的表达水平在正常对照组和PD或DLB患者之间没有差异。我们进一步利用小鼠模型来研究α-突触核蛋白过表达对这些蛋白质的影响，并发现在9周龄时，α-突触核蛋白转基因小鼠中的TSC 2相对于野生型小鼠显著增加，但在30周龄时没有。结合野生型小鼠中这些分子随年龄逐渐增加的表达数据，这些发现表明自噬调节剂被掺入LB中，并且这些蛋白质的表达可以通过包括衰老在内的各种因素增加。
Neurodegenerative disorders such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are characterized by impairment of autophagy. Cellular survival is dependent on efficient clearance of phosphorylated alpha-synuclein, which accumulates as fibrils in the neuronal cytoplasm as Lewy bodies (LBs). The forkhead box O 1 (FOXO1) is a member of the FOXO family that functions in various intracellular processes including regulation of autophagy. Transcriptional activation of FOXO1 has been reported to initiate autophagy by inhibiting the expression of Mechanistic Target of Rapamycin (mTOR), mediated by sestrin 3 (SESN3) and tuberous sclerosis complex 2 (TSC2). Although many autophagy-related proteins are known to be incorporated into LBs, no report has documented the involvement of these autophagy modulators (FOXO1, SESN3 and TSC2) in the pathogenesis of PD and DLB. In the present study, we performed immunostaining and Western blot analysis using the brains of normal controls and patients with PD and DLB in order to clarify the involvement of FOXO1, SESN3 and TSC2 in LBs. Our study demonstrated for the first time the presence of FOXO1, SESN3 and TSC2 in brainstem-type LBs. The expression levels of these proteins in the brain did not differ between the normal controls and patients with PD or DLB. We further utilized mice model to investigate the effect of alpha-synuclein overexpression on these proteins, and found that TSC2 was significantly increased in alpha-synuclein transgenic mice relative to wild type mice at 9 weeks of age, but not at 30 weeks of age. Together with expression data showing gradual increase of these molecules with age in wild type mice, these findings suggest that autophagy modulators are incorporated into LBs and that the expression of these proteins can be increased by various factors including aging.