Salamon Andras, Torok Rita, Sumegi Evelin, Boros Fanni, Pesei Zsofia Gabriella, Fort Molnar Mate, Veres Gabor, Zadori Denes, Vecsei Laszlo, Klivenyi Peter
Department of Neurology, University of Szeged, Semmelweis u. 6, H-6725, Szeged, Hungary.
Department of Neurology, University of Szeged, Semmelweis u. 6, H-6725, Szeged, Hungary; MTA-SZTE Neuroscience Research Group of the Hungarian Academy of Sciences and University of Szeged, Semmelweis u. 6, H-6725, Szeged, Hungary.
Neurosci Lett. 2019 Apr 17;698:13-18. doi: 10.1016/j.neulet.2019.01.003. Epub 2019 Jan 3.
Proper mitochondrial function is crucial for intact cellular homeostasis. Mitochondrial dysfunction is clearly involved in the pathogenesis of most neurodegenerative- and age-related chronic disorders. The aim of this study is to stimulate cellular production of important compounds of mitochondrial biogenesis, namely in the peroxisome proliferator-activated receptor-gamma coactivator (PGC)- and Sirtuin (SIRT)-systems. We studied the effect of cold challenge and training on the mRNA expression levels of some compounds of these systems in different brain areas of mice. With regard to the PGC-system, the mRNA levels of the full- and N-truncated isoforms, and those of the two promoters (brain-specific, reference) were measured. In case of Sirtuins, the mRNA levels of SIRT1 and SIRT3-M1/M2/M3 were assessed. We found the following expression level alterations: cooling resulted in the elevation of cortical SIRT3-M1 levels and the decrease of cerebellar SIRT3-M3 levels after 200 min. 900 min of cold exposure resulted in the reduction of cortical SIRT1 and striatal SIRT3-M1 levels. A prominent elevation could be observed in the levels of all PGC-1α isoforms in the cerebellum after 12 days of training. The 12 days of exercise resulted in increased cerebellar SIRT3-M1 and SIRT3-M2 mRNA levels as well. Although the efficacy of cooling core body and brain temperature is questionable, we found that training exerted a clear effect. The cause of the prominent cerebellar elevation of PGC-, and Sirtuin isoforms could be an increase in synaptic plasticity between Purkinje cells, which facilitates better motor coordination and more precise movement integration. We propose that these systems may serve as promising targets for future therapeutic studies in neurodegenerative diseases.
正常的线粒体功能对于维持完整的细胞内环境稳定至关重要。线粒体功能障碍显然与大多数神经退行性疾病和与年龄相关的慢性疾病的发病机制有关。本研究的目的是刺激细胞产生线粒体生物合成的重要化合物，即过氧化物酶体增殖物激活受体γ共激活因子（PGC）和沉默调节蛋白（SIRT）系统中的化合物。我们研究了冷刺激和训练对小鼠不同脑区这些系统中某些化合物mRNA表达水平的影响。对于PGC系统，测量了全长和N端截短异构体以及两个启动子（脑特异性、参考）的mRNA水平。对于沉默调节蛋白，评估了SIRT1和SIRT3-M1/M2/M3的mRNA水平。我们发现了以下表达水平变化：冷却200分钟后，皮质SIRT3-M1水平升高，小脑SIRT3-M3水平降低。冷暴露900分钟导致皮质SIRT1和纹状体SIRT3-M1水平降低。训练12天后，小脑中所有PGC-1α异构体的水平均显著升高。运动12天也导致小脑SIRT3-M1和SIRT3-M2 mRNA水平升高。尽管降低核心体温及脑温的效果存在疑问，但我们发现训练产生了明显的效果。PGC和沉默调节蛋白异构体在小脑中显著升高的原因可能是浦肯野细胞之间突触可塑性增加，这有助于更好的运动协调和更精确的运动整合。我们认为，这些系统可能成为未来神经退行性疾病治疗研究的有希望的靶点。
