Dana-Farber癌症研究所的科学家提出了一项新报告,发现了脑部开启保护神经细胞免受毒性自由基影响的系统,这些自由基是细胞代谢的废物,与一些退化性脑部疾病、心脏病发作、中风、癌症,和老化有关。
研究员人员表示,研究结果显示,也许可以利用加强脑部抗氧化系统的药物,来治疗目前无药可医的疾病如帕金森氏症、亨丁顿氏症及阿兹海默症。研究作者Bruce Spiegelman和同事利用小鼠模型发现,一种调控蛋白质PGC-1a,是自由基或反应性氧分子累积时,启动脑部抗氧化系统的开关,PGC-1a的启动可以保护细胞免于受到影响。
研究人员目前正在筛检可以刺激脑细胞中PGC-1a表现的化合物,并且探索是否会造成任何有害的副作用。
PGC-1a于1998年第一次在Dana-Farber 实验室由Spiegelman发现,当时研究人员指出,PGC-1a是一种转录的共活化剂。之后研究人员又发现PGC-1a在代谢过程和肌肉功能中扮演着重要的调控角色,也是与糖尿病有关的分子。
而这份报告第一次证实,PGC-1a可以驾驭粒线体生产能量,并引起细胞清除毒性自由基的机制。当自由基增加时,它们的毒性会使细胞获得制造更多PGC-1a的讯息,反过来使抗氧化防御机制运作。经由这个机制,身体可以加速粒线体形成,并同时抑制反应性氧分子的制造。这项研究结果将发表于10月20 日的Cell中。
英文原文:
Analysis:Protein helps brain 'clean house'
BOSTON, Oct. 20 (UPI) -- PGC-1a, a protein that regulates energy production in cells, has now been proven to help the brain clear itself of free radicals that damage its neurons.
Since free radical build-up is found in the brains of people with Alzheimer's disease, Parkinson's disease, Huntington's chorea, and ALS (Lou Gehrig's disease), finding ways to stimulate PGC-1a production may help protect people against these devastating conditions or halt them once they have begun.
Bruce Spiegelman, lead author of the study, and his colleagues at the Dana-Farber Cancer Institute first discovered PGC-1a in 1998 and described it as a master regulator of energy production in the cells' powerhouses, the mitochondria.
Subsequent research around the world revealed that the protein also played a role in muscle function, the development of diabetes, and a variety of other metabolic processes.
PGC-1a's intervention in free radical build-up seems to be linked to its effect on the mitochondria. Free radicals, or reactive oxygen species, are a normal waste product of mitochondrial energy production. When the protein increases activity in the mitochondria, it also increases the production of antioxidants, which naturally remove free radicals from the body.
"With this mechanism, the body can speed up mitochondrial formation and at the same time suppress the creation of reactive oxygen species, which are known to be terribly damaging to the cell," Spiegelman explained. "In this respect, the cell could be compared to a self-cleaning oven -- but one that becomes less efficient with age and in certain diseases."
In their current research, the investigators exposed normal mice and mice that lacked the ability to produce PGC-1a to a nerve toxin that accelerates the production of free radicals. The mice who couldn't produce PGC-1a suffered more brain damage because they couldn't clear the radicals from their system. They then caused mouse and human brain cells cultured in the laboratory to make 40 times the normal amount of PGC-1a, and exposed them to increasing amounts of paraquat or hydrogen peroxide that cause oxidative stress and cell damage.
More brain cells with high levels of PGC-1a survived the assault than normal cells that didn't have the ability to augment their defenses.
The team is now screening drugs to find compounds that could increase PGC-1a levels in brain cells and other areas of the body, since free radical damage has also been linked to heart attacks, strokes, cancer, and aging.
Mark Mehler, director of the Institute for Brain Disorders and Neural Regeneration at the Albert Einstein College of Medicine, was enthusiastic about the work.
"This is a beautifully done study and impacts two important areas: neurodegenerative diseases that have eluded our best abilities to figure them out, and the role of the brain in peripheral energy metabolism and the regulation of body weight and food intake," Mehler told United Press International. "People with neurodegenerative diseases such as Alzheimer's and Parkinson's also have significant metabolic abnormalities, but we have not had a good mechanistic understanding of why that occurred. Now we do. PGC-1a is what's called a modular protein that binds to a series of cofactors and plays many different roles. Finding a way to modulate its expression could protect against the onset of these devastating neurological diseases and also allow us to treat the metabolic derangements that accompany them."
Joe Beckman, a member of the Linus Pauling Institute and the director of the Environmental Health Science Center at Oregon State University, told UPI he was intrigued by the study as well.
"Being able to stimulate antioxidant defenses in the brain is something we really want to be able to do," Beckman said. "This study shows us a way to help the body to increase its natural antioxidants and its ability to handle stress."