Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York-Presbyterian Hospital, New York, NY 10065, USA.
PPAR Res. 2008;2008:418765. doi: 10.1155/2008/418765.
Amyotrophic lateral sclerosis (ALS) is a debilitating and one of the most common adult-onset neurodegenerative diseases with the prevalence of about 5 per 100 000 individuals. It results in the progressive loss of upper and lower motor neurons and leads to gradual muscle weakening ultimately causing paralysis and death. ALS has an obscure cause and currently no effective treatment exists. In this review, a potentially important pathway is described that can be activated by peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists and has the ability to block the neuropathological damage caused by inflammation in ALS and possibly in other neudegenerative diseases like Huntington's disease (HD). Neuroinflammation is a common pathological feature in neurodegenerative diseases. Therefore, PPAR-gamma agonists are thought to be neuroprotective in ALS and HD. We and others have tested the neuroprotective effect of pioglitazone (Actos), a PPAR-gamma agonist, in G93A SOD1 transgenic mouse model of ALS and found significant increase in survival of G93A SOD1 mice. These findings suggest that PPAR-gamma may be an important regulator of neuroinflammation and possibly a new target for the development of therapeutic strategies for ALS. The involvement of PPAR-gamma in HD is currently under investigation, one study finds that the treatment with rosiglitazone had no protection in R6/2 transgenic mouse model of HD. PPAR-gamma coactivator-1alpha (PGC-1alpha) is a transcriptional coactivator that works together with combination of other transcription factors like PPAR-gamma in the regulation of mitochondrial biogenesis. Therefore, PPAR-gamma is a possible target for ALS and HD as it functions as transcription factor that interacts with PGC-1alpha. In this review, the role of PPAR-gamma in ALS and HD is discussed based on the current literature and hypotheses.
肌萎缩侧索硬化症（ALS）是一种使人衰弱的、最常见的成人发病的神经退行性疾病之一，其患病率约为每 10 万人中有 5 人。它导致上运动神经元和下运动神经元的进行性丧失，并导致肌肉逐渐减弱，最终导致瘫痪和死亡。ALS 的病因不明确，目前尚无有效的治疗方法。在这篇综述中，描述了一条可能很重要的途径，该途径可被过氧化物酶体增殖物激活受体-γ（PPAR-γ）激动剂激活，并具有阻止 ALS 中炎症引起的神经病理学损伤的能力，在其他神经退行性疾病（如亨廷顿病（HD））中也可能如此。神经炎症是神经退行性疾病的共同病理特征。因此，PPAR-γ 激动剂被认为对 ALS 和 HD 具有神经保护作用。我们和其他人已经在 G93A SOD1 转基因 ALS 小鼠模型中测试了吡格列酮（Actos），一种 PPAR-γ 激动剂的神经保护作用，发现 G93A SOD1 小鼠的存活率显著提高。这些发现表明，PPAR-γ 可能是神经炎症的重要调节剂，并且可能是开发 ALS 治疗策略的新靶点。PPAR-γ 在 HD 中的参与目前正在研究中，一项研究发现，罗格列酮治疗对 R6/2 转基因 HD 小鼠模型没有保护作用。过氧化物酶体增殖物激活受体-γ 共激活因子-1α（PGC-1α）是一种转录共激活因子，它与 PPAR-γ 等其他转录因子一起在调节线粒体生物发生中起作用。因此，PPAR-γ 是 ALS 和 HD 的一个可能的靶点，因为它作为与 PGC-1α 相互作用的转录因子发挥作用。在这篇综述中，根据目前的文献和假设，讨论了 PPAR-γ 在 ALS 和 HD 中的作用。
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