MRC Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9EH, UK.
Biochem J. 2011 Jan 1;433(1):19-29. doi: 10.1042/BJ20101323.
One of the major current challenges to both medicine and neuroscience is the treatment of neurodegenerative diseases, which pose an ever-increasing medical, social and economic burden in the developed world. These disorders, which include Alzheimer's, Huntington's and Parkinson's diseases, and the rarer prion diseases, are separate entities clinically but have common features, including aggregates of misfolded proteins and varying patterns of neurodegeneration. A key barrier to effective treatment is that patients present clinically with advanced, irreversible, neuronal loss. Critically, mechanisms of neurotoxicity are poorly understood. Prevention of neuronal loss, ideally by targeting underlying pathogenic mechanisms, must be the aim of therapy. The present review describes the rationale and experimental approaches that have allowed such prevention, rescuing neurons in mice with prion disease. This rescue cured animals of a rapidly fatal neurodegenerative condition, resulting in symptom-free survival for their natural lifespan. Early pathological changes were reversed; behavioural, cognitive and neurophysiological deficits were recovered; and there was no neuronal loss. This was achieved by targeting the central pathogenic process in prion disease rather than the presumed toxic species, first by proof-of-principle experiments in transgenic mice and then by treatment using RNA interference for gene knockdown. The results have been a new therapeutic target for prion disease, further insight into mechanisms of prion neurotoxicity and the discovery of a window of reversibility in neuronal damage. Furthermore, the work gives rise to new concepts for treatment strategies for other neurodegenerative disorders, and highlights the need for clinical detection of early neuronal dysfunction, so that similar early rescue can also be achieved for these disorders.
当前，医学和神经科学面临的主要挑战之一是治疗神经退行性疾病，这些疾病在发达国家造成了日益增加的医疗、社会和经济负担。这些疾病包括阿尔茨海默病、亨廷顿病和帕金森病，以及更为罕见的朊病毒病，它们在临床上是不同的实体，但具有共同的特征，包括错误折叠蛋白的聚集和不同模式的神经退行性变。有效治疗的一个关键障碍是，患者在临床上表现为晚期、不可逆转的神经元丧失。至关重要的是，神经毒性的机制还了解甚少。通过针对潜在的致病机制来预防神经元丧失，必须是治疗的目标。本综述描述了允许这种预防的基本原理和实验方法，这些方法已经在朊病毒病的小鼠中挽救了神经元。这种挽救治愈了患有快速致命神经退行性疾病的动物，使它们在其自然寿命内无病生存。早期的病理变化得到逆转；行为、认知和神经生理缺陷得到恢复；没有神经元丧失。这是通过针对朊病毒病的中枢致病过程而不是假定的毒性物质来实现的，首先在转基因小鼠中进行了原理验证实验，然后通过使用 RNA 干扰进行基因敲低来进行治疗。结果为朊病毒病提供了一个新的治疗靶点，进一步深入了解了朊病毒神经毒性的机制，并发现了神经元损伤的可逆转窗口。此外，这项工作为其他神经退行性疾病的治疗策略提供了新的概念，并强调了需要临床检测早期神经元功能障碍，以便为这些疾病也能实现类似的早期挽救。
