A strong consensus has emerged around the role of protein misfolding and aggregation in the pathogenesis of neurodegeneration. Introduction.
A strong consensus has emerged around the role of protein misfolding and aggregation in the pathogenesis of neurodegeneration. Introduction.
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关于蛋白质错误折叠和聚集在神经退行性疾病发病机制中的作用已经形成了强烈的共识。
DOI：
10.1007/s13311-013-0197-2
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Diamond,MarcI
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作者：
Diamond,MarcI
对导致神经退行性疾病主要遗传形式的基因的识别，最初为快速发展治疗带来了希望。然而，尽管我们对基本疾病机制的理解取得了巨大进步，并且建立了多种小鼠模型，但我们仍然没有有效的治疗任何中枢神经系统（CNS）神经退行性疾病的方法。然而，这种严峻的前景现在正在改变。关于蛋白质错误折叠和聚集在神经变性发病机制中的作用，已经形成了强烈的共识。几乎所有主要的年龄依赖性成人神经退行性疾病都以蛋白质聚集体的积累为特征。在确定显性遗传形式的情况下，几乎所有情况下，它们都与沉积在大脑中的蛋白质有关，与这些蛋白质的产生有关（在早老素的情况下），或者与蛋白质质量控制途径有关。因此，有大量的潜在靶点，而与此同时，通过小分子、多肽和基因治疗的干预手段也在迅速发展。本期专题综述涵盖了与蛋白质错误折叠和神经退行性疾病相关的主要主题。这些范围从基础生物学到药物开发和输送的最新进展。问题开始于对神经退行性疾病传播中的朊病毒样机制的新观点（Kaufman和Diamond，见第XX页）。这种神经退行性疾病的发病机制模型是有用的，因为它对细胞内聚集和神经元之间蛋白质聚集的传播的综合作用做出了具体的预测。该模型并没有从根本上改变现有的关于蛋白质聚集机制的实验数据的解释。然而，如果这个模型的基本组成部分得到验证，这将提出新的治疗方法，以前没有设想基于纯粹的细胞自主蛋白质聚集。同样，我们现在越来越具体地了解蛋白质质量控制途径（如自噬）在清除错误折叠蛋白质中的作用（Weihl，第XX页）。我们对清除错误折叠单体和聚集体的不同途径的了解，以及保护机制的复杂性，可以为新的治疗策略提供更好的见解。事实上，多种现有的候选化合物可能被用来促进致病蛋白的清除。虽然蛋白质错误折叠和聚集与许多神经退行性疾病密切相关，但形成非常大的聚集本身并不一定是病理的唯一原因。突触核蛋白在帕金森病和弥漫性路易体痴呆等其他疾病的发病机制中所起的作用已被广泛研究。作为一种细胞内膜相关蛋白，致病性突触核蛋白可能在破坏线粒体稳定以促进神经元易感性方面发挥关键作用（Nakamura，页XX）。这可能为独立于防止大聚集体形成的治疗干预提供了新的可能性。有了研究病理基本机制的模型，我们越来越有能力设计干预措施来修改这些机制，测试潜在的假设，并可能开发治疗线索。由于在较大的生物体中筛选候选基因和小分子是不太可行的，因此长期以来人们一直对细胞病理模型的发展及其用于鉴定候选修饰基因和先导化合物感兴趣。不幸的是，多个屏幕……
The identification of genes that cause dominantly inherited forms of neurodegenerative disease originally led to hope for rapid therapeutic development. However, despite tremendous advances in our understanding about basic disease mechanisms, and the creation of multiple mouse models, we still do not have an effective treatment for any central nervous system (CNS) neurodegenerative disease. This grim outlook is now changing, however. A strong consensus has emerged around the role of protein misfolding and aggregation in the pathogenesis of neurodegeneration. Virtually all major age-dependent neurodegenerative diseases of adults feature accumulation of protein aggregates. Where dominantly inherited forms are identified, in almost all cases they have been linked to the very proteins that deposit within the brain, to the production of those proteins (in the case of the presenilins), or to protein quality control pathways. Consequently, there is an abundance of potential targets, while, at the same time, the means of intervention via small molecules, peptides, and gene therapy has rapidly evolved. This issue features reviews that cover the major topics related to protein misfolding and neurodegenerative disease. These range from basic biology to recent advances in drug development and delivery. The issue begins with new perspectives on prion-like mechanisms in the propagation of neurodegenerative diseases (Kaufman and Diamond, see pages XX). This model of the pathogenesis of neurodegenerative diseases is useful because it makes specific predictions about the combined roles of intracellular aggregation and the spread of protein aggregates between neurons. The model does not fundamentally alter the interpretation of existing experimental data regarding protein aggregation mechanisms. However, should essential components of this model be validated, this will suggest new therapeutic approaches that were not previously envisioned based on purely cell autonomous protein aggregation. Similarly, we now understand in increasingly specific terms the role of protein quality control pathways such as autophagy in clearance of misfolded proteins (Weihl, pages XX). Our knowledge about different pathways involved in the clearance of misfolded monomers versus aggregates, and the complexity of protective mechanisms, can provide better insight into new therapeutic strategies. Indeed, multiple existing candidate compounds might be exploited to promote the clearance of pathogenic proteins.While protein misfolding and aggregation are strongly linked to many neurodegenerative diseases, the formation of very large aggregates themselves is not necessarily the only cause of pathology. Synuclein has now been extensively studied for its role in the pathogenesis of Parkinson disease and other pathologies, such as diffuse Lewy body dementia. As an intracellular membrane-associated protein, pathogenic synuclein may play a key role in destabilizing mitochondria to promote neuronal vulnerability (Nakamura, pages XX). This could suggest new possibilities for therapeutic intervention independent of preventing large aggregate formation. With models to study basic mechanisms of pathology, we are increasingly in a position to design interventions to modify these mechanisms, to test the underlying hypotheses, and possibly to develop therapeutic leads. As it is not so feasible to screen candidate genes and small molecules in larger organisms, there has been longstanding interest in the development of cellular models of pathology, and their use to identify candidate modifier genes and lead compounds. Unfortunately, multiple screens …