Axon Injury-Induced Autophagy Activation Is Impaired in a C. elegans Model of Tauopathy.
Axon Injury-Induced Autophagy Activation Is Impaired in a C. elegans Model of Tauopathy.
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DOI：
10.3390/ijms21228559
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发表时间：
2020-11-13
影响因子：
5.6
通讯作者：
Chen L
中科院分区：
文献类型：
--
作者：
Ko SH;Gonzalez G;Liu Z;Chen L
自噬是一种保守的途径，在正常情况下以及异常和应激条件下的细胞内稳态中发挥关键作用。自噬功能障碍在各种神经退行性疾病中被发现，尽管目前尚不清楚自噬功能障碍是否是神经退行性疾病的贡献者或后果。轴突损伤是一种急性神经元应激，以年龄相关的方式触发自噬反应。在这项研究中，我们研究了损伤触发的自噬反应在线虫的牛变病模型中。我们发现，转基因表达的前聚集型Tau，而不是反聚集型Tau，取消了轴突损伤诱导的自噬激活，导致轴突再生能力降低。此外，在表达前聚集体F3ΔK280Tau的动物中，自噬小泡的轴突运输显著减少，表明Tau聚集损害了自噬调节。重要的是，自噬激活剂雷帕霉素不能恢复自噬模型中总的或运输的自噬小泡的数量。线虫中唯一的Tau同源物PTL-1的缺失也导致损伤诱导的自噬激活，但自噬小泡的基础水平增加。因此，我们证明了Tau的聚集和Tau的耗竭都会导致损伤诱导的自噬反应的破坏，这表明蛋白的异常聚集或微管功能障碍可以调节损伤后神经元的自噬调节。
Autophagy is a conserved pathway that plays a key role in cell homeostasis in normal settings, as well as abnormal and stress conditions. Autophagy dysfunction is found in various neurodegenerative diseases, although it remains unclear whether autophagy impairment is a contributor or consequence of neurodegeneration. Axonal injury is an acute neuronal stress that triggers autophagic responses in an age-dependent manner. In this study, we investigate the injury-triggered autophagy response in a C. elegans model of tauopathy. We found that transgenic expression of pro-aggregant Tau, but not the anti-aggregant Tau, abolished axon injury-induced autophagy activation, resulting in a reduced axon regeneration capacity. Furthermore, axonal trafficking of autophagic vesicles were significantly reduced in the animals expressing pro-aggregant F3ΔK280 Tau, indicating that Tau aggregation impairs autophagy regulation. Importantly, the reduced number of total or trafficking autophagic vesicles in the tauopathy model was not restored by the autophagy activator rapamycin. Loss of PTL-1, the sole Tau homologue in C. elegans, also led to impaired injury-induced autophagy activation, but with an increased basal level of autophagic vesicles. Therefore, we have demonstrated that Tau aggregation as well as Tau depletion both lead to disruption of injury-induced autophagy responses, suggesting that aberrant protein aggregation or microtubule dysfunction can modulate autophagy regulation in neurons after injury.
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影响因子：
16
作者：
Kroemer G;Mariño G;Levine B
通讯作者：
Levine B
影响因子：
3.5
作者：
Fatouros, Chronis;Pir, Ghulam Jeelani;Baumeister, Ralf
通讯作者：
Baumeister, Ralf
自噬诱导可稳定微管并促进脊髓损伤后轴突再生。
DOI：
10.1073/pnas.1611282113
发表时间：
2016-10-04
影响因子：
11.1
作者：
He, Miao;Ding, Yuetong;Luo, Zhen-Ge
通讯作者：
Luo, Zhen-Ge
影响因子：
4.6
作者：
Kim S;Choi KJ;Cho SJ;Yun SM;Jeon JP;Koh YH;Song J;Johnson GV;Jo C
通讯作者：
Jo C
影响因子：
1.5
作者：
Kimura, Shunsuke;Noda, Takeshi;Yoshimori, Tamotsu
通讯作者：
Yoshimori, Tamotsu