Parkin reverses TDP-43-induced cell death and failure of amino acid homeostasis.
Parkin reverses TDP-43-induced cell death and failure of amino acid homeostasis.
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DOI：
10.1111/jnc.12630
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发表时间：
2014-04
影响因子：
4.7
通讯作者：
Moussa CE
中科院分区：
文献类型：
--
作者：
Hebron M;Chen W;Miessau MJ;Lonskaya I;Moussa CE
E3泛素连接酶帕金（Parkin）在许多神经退行性疾病的发病机制中起着核心作用。帕金促进特定的泛素化并影响TDP - 43的定位，TDP - 43控制着数千种信使核糖核酸（mRNAs）的翻译。在此，我们利用高频13C核磁共振波谱技术检测了慢病毒介导的帕金和TDP - 43表达对大鼠运动皮层氨基酸代谢的影响。TDP - 43表达使谷氨酸水平升高，使包括谷氨酰胺、天冬氨酸、亮氨酸和异亮氨酸在内的其他氨基酸水平降低，并损害线粒体三羧酸（TCA）循环。TDP - 43诱导乳酸积累，并改变兴奋性（谷氨酸）和抑制性（γ - 氨基丁酸，GABA）神经递质之间的平衡。帕金恢复了氨基酸水平、神经递质平衡和TCA循环代谢，使神经元从TDP - 43诱导的凋亡死亡中被挽救出来。此外，TDP - 43表达导致4E - BP水平升高，可能改变翻译控制并使氨基酸合成失调；而帕金逆转了TDP - 43对4E - BP信号通路的影响。综上所述，这些数据表明帕金可能影响TDP - 43的定位，并减轻其对4E - BP信号传导和氨基酸内稳态丧失的影响。
The E3 ubiquitin ligase Parkin plays a central role in the pathogenesis of many neurodegenerative diseases. Parkin promotes specific ubiquitination and affects the localization of TDP-43, which controls the translation of thousands of mRNAs. Here we tested the effects of lentiviral Parkin and TDP-43 expression on amino acid metabolism in the rat motor cortex using high frequency 13C NMR spectroscopy. TDP-43 expression increased glutamate levels, decreased the levels of other amino acids, including glutamine, aspartate, leucine and isoleucine, and impaired mitochondrial TCA cycle. TDP-43 induced lactate accumulation and altered the balance between excitatory (glutamate) and inhibitory (GABA) neurotransmitters. Parkin restored amino acid levels, neurotransmitter balance and TCA cycle metabolism, rescuing neurons from TDP-43-induced apoptotic death. Furthermore, TDP-43 expression led to an increase in 4E-BP levels, perhaps altering translational control and deregulating amino acid synthesis; while Parkin reversed the effects of TDP-43 on the 4E-BP signaling pathway. Taken together, these data suggest that Parkin may affect TDP-43 localization and mitigate its effects on 4E-BP signaling and loss of amino acid homeostasis.
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影响因子：
4.8
作者：
Grolleau, A;Bowman, J;Beretta, L
通讯作者：
Beretta, L
影响因子：
56.9
作者：
Kwiatkowski, T. J., Jr.;Bosco, D. A.;Brown, R. H., Jr.
通讯作者：
Brown, R. H., Jr.
影响因子：
3.5
作者：
Burns, Mark P.;Zhang, Lihua;Moussa, Charbel E. -H.
通讯作者：
Moussa, Charbel E. -H.
影响因子：
56.9
作者：
Huber, KM;Kayser, MS;Bear, MF
通讯作者：
Bear, MF
影响因子：
56.9
作者：
Kang, HJ;Schuman, EM
通讯作者：
Schuman, EM