Enhancing nucleotide metabolism protects against mitochondrial dysfunction and neurodegeneration in a PINK1 model of Parkinson's disease.
Enhancing nucleotide metabolism protects against mitochondrial dysfunction and neurodegeneration in a PINK1 model of Parkinson's disease.
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DOI：
10.1038/ncb2901
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发表时间：
2014-02
影响因子：
21.3
通讯作者：
中科院分区：
文献类型：
--
作者：
PINK1 突变会导致早发性帕金森病 (PD)。对果蝇的研究强调 Pink1 缺失导致的线粒体功能障碍是 PD 发病机制的一个核心机制。在这里，我们展示了对果蝇pink1突变体转录变化的整体分析揭示了参与核苷酸代谢的基因的上调，这对神经元线粒体DNA合成至关重要。在携带 PINK1 突变的 PD 患者的大脑中也检测到了这些关键的转录变化。我们证明，pink1 突变果蝇神经元中核苷酸挽救途径的遗传增强可以挽救线粒体损伤。此外，增强核苷酸库的药理学方法可减少 Pink1 缺陷引起的线粒体功能障碍。我们得出的结论是，Pink1 的丢失会引起先前未识别的代谢重编程途径的激活，从而增加核苷酸池并促进线粒体生物发生。我们提出，增强核苷酸合成途径的靶向策略可能会逆转线粒体功能障碍，并挽救帕金森病以及可能与线粒体损伤相关的其他疾病的神经变性。
Mutations in PINK1 cause early-onset Parkinson’s disease (PD). Studies in Drosophila melanogaster have highlighted mitochondrial dysfunction on loss of Pink1 as a central mechanism of PD pathogenesis. Here we show that global analysis of transcriptional changes in Drosophila pink1 mutants reveals an upregulation of genes involved in nucleotide metabolism, critical for neuronal mitochondrial DNA synthesis. These key transcriptional changes were also detected in brains of PD patients harbouring PINK1 mutations. We demonstrate that genetic enhancement of the nucleotide salvage pathway in neurons of pink1 mutant flies rescues mitochondrial impairment. In addition, pharmacological approaches enhancing nucleotide pools reduce mitochondrial dysfunction caused by Pink1 deficiency. We conclude that loss of Pink1 evokes the activation of a previously unidentified metabolic reprogramming pathway to increase nucleotide pools and promote mitochondrial biogenesis. We propose that targeting strategies enhancing nucleotide synthesis pathways may reverse mitochondrial dysfunction and rescue neurodegeneration in PD and, potentially, other diseases linked to mitochondrial impairment.
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影响因子：
5.3
作者：
Wills, Jonathan;Jones, Jessica;Haggerty, Thomas;Duka, Valeriy;Joyce, Jeffrey N.;Sidhu, Anita
通讯作者：
Sidhu, Anita
DOI：
10.1146/annurev.pathol.3.121806.151529
发表时间：
2009
期刊：
Annual review of pathology
影响因子：
--
作者：
Lu B;Vogel H
通讯作者：
Vogel H
DOI：
10.1073/pnas.0913485107
发表时间：
2010-03-16
影响因子：
11.1
作者：
Ziviani, Elena;Tao, Ran N.;Whitworth, Alexander J.
通讯作者：
Whitworth, Alexander J.
PINK1 在健康和疾病中发挥作用。
影响因子：
11.1
作者：
Deas, Emma;Plun-Favreau, Helene;Wood, Nicholas W.
通讯作者：
Wood, Nicholas W.
影响因子：
64.8
作者：
Clark, Ira E.;Dodson, Mark W.;Guo, Ming
通讯作者：
Guo, Ming