A transition to degeneration triggered by oxidative stress in degenerative disorders.
A transition to degeneration triggered by oxidative stress in degenerative disorders.
复制标题
在退行性疾病中由氧化应激引发的向退行性疾病的转变。
DOI：
10.1038/s41380-020-00943-9
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发表时间：
2021-03
影响因子：
11
通讯作者：
McNew JA
中科院分区：
文献类型：
--
作者：
Stern M;McNew JA
尽管在神经退行性和肌肉退行性疾病的发展过程中，许多信号通路的活性被失调，但导致退行性疾病的细胞事件的确切序列还没有完全阐明。两个特别感兴趣的激酶，促进生长的Tor激酶和能量感受器AMPK，似乎在退行性变过程中显示出相互的活性变化，报告了Tor活性的增加和AMPK活性的降低。这些活性的变化被预测为通过减弱自噬而导致退化，导致未折叠蛋白聚集体的积累和功能障碍的线粒体，从而增加活性氧物种(ROS)的产生，最终导致氧化损伤。在这里，我们认为，这种增加的ROS产生不仅导致氧化损伤，而且最终诱导氧化应激反应，重新激活氧化还原敏感的AMPK和激活氧化还原敏感的应激激酶JNK。这些激酶的激活会重新激活自噬。由于在这一后期阶段，细胞中充满了功能失调的线粒体和蛋白质聚集体，这是自噬的目标，这种自噬重新激活会导致退化。这里提出的机制强调了退化的过程是动态的，随着退化的进展，失调的信号通路会随着时间的推移而改变，并可以从有害转化为有益，反之亦然。
Although the activities of many signaling pathways are dysregulated during the progression of neurodegenerative and muscle degeneration disorders, the precise sequence of cellular events leading to degeneration have not been fully elucidated. Two kinases of particular interest, the growth-promoting Tor kinase and the energy sensor AMPK, appear to show reciprocal changes in activity during degeneration, with increased Tor activity and decreased AMPK activity reported. These changes in activity have been predicted to cause degeneration by attenuating autophagy, leading to accumulation of unfolded protein aggregates and dysfunctional mitochondria, the consequent increased production of reactive oxygen species (ROS), and ultimately oxidative damage. Here we propose that this increased ROS production not only causes oxidative damage but also ultimately induces an oxidative stress response that reactivates the redox-sensitive AMPK and activates the redox-sensitive stress kinase JNK. Activation of these kinases re-activates autophagy. Because at this late stage, cells have become filled with dysfunctional mitochondria and protein aggregates, which are autophagy targets, this autophagy reactivation induces degeneration. The mechanism proposed here emphasizes that the process of degeneration is dynamic, that dysregulated signaling pathways change over time and can transition from deleterious to beneficial and vice versa as degeneration progresses.
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影响因子：
3.8
作者：
Acevedo-Torres, Karina;Berrios, Lexsy;Rosario, Nydia;Dufault, Vanessa;Skatchkov, Serguei;Eaton, Misty J.;Torres-Ramos, Carlos A.;Ayala-Torres, Sylvette
通讯作者：
Ayala-Torres, Sylvette
影响因子：
4.3
作者：
Chaplot, Kriti;Pimpale, Lokesh;Ratnaparkhi, Girish S.
通讯作者：
Ratnaparkhi, Girish S.
影响因子：
29
作者：
Bjedov I;Toivonen JM;Kerr F;Slack C;Jacobson J;Foley A;Partridge L
通讯作者：
Partridge L
影响因子：
3.7
作者：
Crews L;Spencer B;Desplats P;Patrick C;Paulino A;Rockenstein E;Hansen L;Adame A;Galasko D;Masliah E
通讯作者：
Masliah E
DOI：
10.1523/jneurosci.5519-10.2011
发表时间：
2011-02-09
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Cheng HC;Kim SR;Oo TF;Kareva T;Yarygina O;Rzhetskaya M;Wang C;During M;Talloczy Z;Tanaka K;Komatsu M;Kobayashi K;Okano H;Kholodilov N;Burke RE
通讯作者：
Burke RE