Proteostasis and Movement Disorders: Parkinson's Disease and Amyotrophic Lateral Sclerosis
Proteostasis and Movement Disorders: Parkinson's Disease and Amyotrophic Lateral Sclerosis
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DOI：
10.1101/cshperspect.a007500
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发表时间：
2011-10-01
影响因子：
7.2
通讯作者：
Ringe, Dagmar
中科院分区：
文献类型：
--
作者：
Bosco, Daryl A.;LaVoie, Matthew J.;Ringe, Dagmar
帕金森病（PD）是一种运动障碍疾病，在美国有超过100万人患病；肌萎缩侧索硬化症（ALS，又称卢伽雷氏病）发病率较低，但也较高。这两种疾病有时会同时出现，因此进行比较研究很有意义。ALS和PD都是神经退行性疾病，其特征是存在神经元内包涵体；然而，受影响的神经元类别不同，疾病之间包涵体中的主要蛋白质也不同，在某些情况下，同一疾病的不同类型中也存在差异。这些观察结果可能表明，蛋白质稳态途径改变这一更通用的方法在治疗这些疾病方面将是一种强有力的手段。通过研究人类遗传学结果、模式生物研究以及两种疾病所涉及蛋白质的生化和生物物理特性，我们发现大多数帕金森病病例可被视为由神经元小蛋白α - 突触核蛋白的错误折叠以及自身聚集形成有毒物质所引起，并且蛋白质稳态策略可能对这种疾病有价值。对于ALS，情况要复杂得多，也不那么明确；现有数据最符合这样一种观点，即ALS实际上可能是一类疾病，表现相似但由不同且无重叠的原因引起，包括一些正确折叠的蛋白质的错误定位以及RNA质量控制途径的紊乱。将蛋白质稳态方法应用于这种疾病可能需要重新思考或拓宽蛋白质稳态的概念。
Parkinson's disease (PD) is a movement disorder that afflicts over one million in the U.S.; amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) is less prevalent but also has a high incidence. The two disorders sometimes present together, making a comparative study of interest. Both ALS and PD are neurodegenerative diseases, and are characterized by the presence of intraneuronal inclusions; however, different classes of neurons are affected and the primary protein in the inclusions differs between the diseases, and in some cases is different in distinct forms of the same disease. These observations might suggest that the more general approach of proteostasis pathway alteration would be a powerful one in treating these disorders. Examining results from human genetics and studies in model organisms, as well as from biochemical and biophysical characterization of the proteins involved in both diseases, we find that most instances of PD can be considered as arising from the misfolding, and self-association to a toxic species, of the small neuronal protein alpha-synuclein, and that proteostasis strategies are likely to be of value for this disorder. For ALS, the situation is much more complex and less clear-cut; the available data are most consistent with a view that ALS may actually be a family of disorders, presenting similarly but arising from distinct and nonoverlapping causes, including mislocalization of some properly folded proteins and derangement of RNA quality control pathways. Applying proteostasis approaches to this disease may require rethinking or broadening the concept of what proteostasis means.