当前位置: X-MOL 学术Sci. Transl. Med. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
PPARδ activation by bexarotene promotes neuroprotection by restoring bioenergetic and quality control homeostasis
Science Translational Medicine ( IF 15.8 ) Pub Date : 2017-12-06 , DOI: 10.1126/scitranslmed.aal2332
Audrey S. Dickey 1 , Dafne N. Sanchez 1 , Martin Arreola 1 , Kunal R. Sampat 1 , Weiwei Fan 2 , Nicolas Arbez 3 , Sergey Akimov 3 , Michael J. Van Kanegan 4 , Kohta Ohnishi 1 , Stephen K. Gilmore-Hall 1 , April L. Flores 1 , Janice M. Nguyen 1 , Nicole Lomas 1 , Cynthia L. Hsu 1 , Donald C. Lo 4 , Christopher A. Ross 3, 5 , Eliezer Masliah 6, 7 , Ronald M. Evans 2, 8 , Albert R. La Spada 1, 7, 9, 10, 11
Affiliation  

Neurons must maintain protein and mitochondrial quality control for optimal function, an energetically expensive process. The peroxisome proliferator–activated receptors (PPARs) are ligand-activated transcription factors that promote mitochondrial biogenesis and oxidative metabolism. We recently determined that transcriptional dysregulation of PPARδ contributes to Huntington’s disease (HD), a progressive neurodegenerative disorder resulting from a CAG-polyglutamine repeat expansion in the huntingtin gene. We documented that the PPARδ agonist KD3010 is an effective therapy for HD in a mouse model. PPARδ forms a heterodimer with the retinoid X receptor (RXR), and RXR agonists are capable of promoting PPARδ activation. One compound with potent RXR agonist activity is the U.S. Food and Drug Administration–approved drug bexarotene. We tested the therapeutic potential of bexarotene in HD and found that bexarotene was neuroprotective in cellular models of HD, including medium spiny-like neurons generated from induced pluripotent stem cells (iPSCs) derived from patients with HD. To evaluate bexarotene as a treatment for HD, we treated the N171-82Q mouse model with the drug and found that bexarotene improved motor function, reduced neurodegeneration, and increased survival. To determine the basis for PPARδ neuroprotection, we evaluated metabolic function and noted markedly impaired oxidative metabolism in HD neurons, which was rescued by bexarotene or KD3010. We examined mitochondrial and protein quality control in cellular models of HD and observed that treatment with a PPARδ agonist promoted cellular quality control. By boosting cellular activities that are dysfunctional in HD, PPARδ activation may have therapeutic applications in HD and potentially other neurodegenerative diseases.



中文翻译:

贝沙罗汀激活的PPARδ通过恢复生物能和质量控制稳态来促进神经保护

神经元必须维持蛋白质和线粒体的质量控制,以实现最佳功能,这是一个耗费能量的过程。过氧化物酶体增殖物激活受体(PPAR)是配体激活的转录因子,可促进线粒体的生物发生和氧化代谢。我们最近确定,PPARδ的转录失调会导致亨廷顿氏病(HD),这是一种由亨廷顿基因中的CAG-聚谷氨酰胺重复扩增引起的进行性神经退行性疾病。我们记录了PPARδ激动剂KD3010是在小鼠模型中HD的有效疗法。PPARδ与维甲酸X受体(RXR)形成异二聚体,并且RXR激动剂能够促进PPARδ活化。具有有效RXR激动剂活性的一种化合物是美国食品和药物管理局批准的药物贝沙罗汀。我们测试了Bexarotene在HD中的治疗潜力,发现Bexarotene在HD细胞模型中具有神经保护作用,包括从HD患者衍生的诱导性多能干细胞(iPSC)产生的中等棘状神经元。为了评估贝沙罗汀作为HD的治疗方法,我们用该药物处理了N171-82Q小鼠模型,发现贝沙罗汀改善了运动功能,减少了神经变性,并提高了生存率。为了确定PPARδ神经保护的基础,我们评估了代谢功能,并注意到HD神经元中氧化代谢的明显受损,这被贝沙罗汀或KD3010挽救了。我们检查了高清细胞模型中的线粒体和蛋白质质量控​​制,并观察到用PPARδ激动剂进行的治疗促进了细胞质量控制。

更新日期:2017-12-06
down
wechat
bug