PPARγ/PGC1α signaling as a potential therapeutic target for mitochondrial biogenesis in neurodegenerative disorders.
PPARγ/PGC1α signaling as a potential therapeutic target for mitochondrial biogenesis in neurodegenerative disorders.
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PPARγ/PGC 1 α信号作为神经退行性疾病线粒体生物合成的潜在治疗靶点
DOI：
10.1016/j.pharmthera.2020.107705
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发表时间：
2021-03
影响因子：
13.5
通讯作者：
Elsworth JD
中科院分区：
文献类型：
--
作者：
Jamwal S;Blackburn JK;Elsworth JD
神经退行性疾病代表了一些最具破坏性的神经系统疾病，其特征是神经元结构和功能的逐渐丧失。目前对神经退行性疾病的治疗仅限于对症治疗，而不是疾病修饰干预，这强调了对改进方法的迫切需要。大量证据表明，线粒体功能受损在许多神经退行性疾病的发病机制中起着至关重要的作用，因此线粒体中的生化因子被认为是基于药物治疗的有希望的靶点。过氧化物酶体增殖物激活受体-γ (PPARγ)是配体诱导的转录因子，参与调节多种基因，包括过氧化物酶体增殖物激活受体γ共激活因子-1 α (PGC1α)。本文综述了支持PPARγ-PGC1α协调上调神经元线粒体生物发生所需基因表达能力的证据，并为进一步探索靶向线粒体生物发生治疗神经退行性疾病的潜在益处提供了方向。我们强调了NRF2、解偶联蛋白-2 （UCP2）和对氧磷酶-2 （PON2）信号在介导pgc1 α-诱导的线粒体生物发生中的关键作用。此外，PPARγ调节剂在帕金森病（PD）、阿尔茨海默病（AD）和亨廷顿病（HD）临床试验中的应用状况也已汇编。本综述的总体目的是更新和批评我们对PPARγ-PGC1α-NRF2在诱导线粒体生物发生中的作用的理解，以及针对PPARγ-PGC1α-NRF2信号通路的策略建议，以对抗神经退行性疾病中的线粒体功能障碍。
Neurodegenerative diseases represent some of the most devastating neurological disorders, characterized by progressive loss of the structure and function of neurons. Current therapy for neurodegenerative disorders is limited to symptomatic treatment rather than disease modifying interventions, emphasizing the desperate need for improved approaches. Abundant evidence indicates that impaired mitochondrial function plays a crucial role in pathogenesis of many neurodegenerative diseases and so biochemical factors in mitochondria are considered promising targets for pharmacological-based therapies. Peroxisome proliferator-activated receptors-γ (PPARγ) are ligand-inducible transcription factors involved in regulating various genes including peroxisome proliferator-activated receptor gamma co-activator-1 alpha (PGC1α). This review summarizes the evidence supporting the ability of PPARγ-PGC1α to coordinately up-regulate the expression of genes required for mitochondrial biogenesis in neurons and provide directions for future work to explore the potential benefit of targeting mitochondrial biogenesis in neurodegenerative disorders. We have highlighted key roles of NRF2, uncoupling protein-2 (UCP2), and paraoxonase-2 (PON2) signaling in mediating PGC1α-induced mitochondrial biogenesis. In addition, the status of PPARγ modulators being used in clinical trials for Parkinson’s disease (PD), Alzheimer’s disease (AD) and Huntington’s disease (HD) has been compiled. The overall purpose of this review is to update and critique our understanding of the role of PPARγ-PGC1α-NRF2 in the induction of mitochondrial biogenesis together with suggestions for strategies to target PPARγ-PGC1α-NRF2 signaling in order to combat mitochondrial dysfunction in neurodegenerative disorders.
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影响因子：
3.7
作者：
Chang JS;Ha K
通讯作者：
Ha K
DOI：
10.1523/jneurosci.3890-09.2009
发表时间：
2009-11-11
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Andrews ZB;Erion D;Beiler R;Liu ZW;Abizaid A;Zigman J;Elsworth JD;Savitt JM;DiMarchi R;Tschoep M;Roth RH;Gao XB;Horvath TL
通讯作者：
Horvath TL
影响因子：
5.3
作者：
Carlos Corona, Juan;Campos de Souza, Senio;Duchen, Michael R.
通讯作者：
Duchen, Michael R.
影响因子：
3.3
作者：
Carta, A. R.;Frau, L.;Carboni, E.
通讯作者：
Carboni, E.
影响因子：
5.3
作者：
Blackburn, Jennifer K.;Curry, Daniel W.;Elsworth, John D.
通讯作者：
Elsworth, John D.