Revisiting protein aggregation as pathogenic in sporadic Parkinson and Alzheimer diseases
Revisiting protein aggregation as pathogenic in sporadic Parkinson and Alzheimer diseases
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DOI：
10.1212/wnl.0000000000006926
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发表时间：
2019-02-12
期刊：
影响因子：
9.9
通讯作者：
Leverenz, James B.
中科院分区：
文献类型：
--
作者：
Espay, Alberto J.;Vizcarra, Joaquin A.;Leverenz, James B.
帕金森病(PD)确诊的金标准是病理发现聚集的α-突触核蛋白进入路易小体，阿尔茨海默病(AD)的病理发现是淀粉样蛋白聚集成斑块，tau过度磷酸化成缠结。在这种基于临床病理的病因学中隐含着这样的假设，即尸检时的病理性蛋白聚集反映了疾病发病时的发病机制。虽然这些聚集体在特殊情况下可能在人类中处于因果路径上(例如，SNCA基因倍增中的聚集性α-突触核蛋白或APP突变中的聚集性β-淀粉样蛋白)，但它们在散发性PD和AD中的死后普遍性表明，它们可能代表了上游机制或对细胞应激的代偿反应的共同结果，以延缓细胞死亡。由于无法实时探测脑组织，这三个蛋白质聚集的概念框架(致病、副现象、保护性)很难解析。虽然在自然状态下既不发生PD也不发生AD的动物模型一贯支持蛋白质聚集的致病作用，而来自人类研究的间接证据则不支持。我们假设(1)目前蛋白质聚集体的生物标记物可能与常见的病理学有关，但与亚组发病机制无关，(2)针对寡聚体或纤维的疾病修改治疗可能是徒劳或有害的，因为这些蛋白质是分子应激下人脑的附属物或保护性的。未来针对神经退行性疾病分子靶向的精确医学努力可能需要分析，而不是基于当前的临床病理标准，而是基于大量深度表型老龄化人口或较小但定义明确的遗传-分子队列产生的生物信号。
The gold standard for a definitive diagnosis of Parkinson disease (PD) is the pathologic finding of aggregated alpha-synuclein into Lewy bodies and for Alzheimer disease (AD) aggregated amyloid into plaques and hyperphosphorylated tau into tangles. Implicit in this clinicopathologic-based nosology is the assumption that pathologic protein aggregation at autopsy reflects pathogenesis at disease onset. While these aggregates may in exceptional cases be on a causal pathway in humans (e.g., aggregated alpha-synuclein in SNCA gene multiplication or aggregated beta-amyloid in APP mutations), their near universality at postmortem in sporadic PD and AD suggests they may alternatively represent common outcomes from upstream mechanisms or compensatory responses to cellular stress in order to delay cell death. These 3 conceptual frameworks of protein aggregation (pathogenic, epiphenomenon, protective) are difficult to resolve because of the inability to probe brain tissue in real time. Whereas animal models, in which neither PD nor AD occur in natural states, consistently support a pathogenic role of protein aggregation, indirect evidence from human studies does not. We hypothesize that (1) current biomarkers of protein aggregates may be relevant to common pathology but not to subgroup pathogenesis and (2) disease-modifying treatments targeting oligomers or fibrils might be futile or deleterious because these proteins are epiphenomena or protective in the human brain under molecular stress. Future precision medicine efforts for molecular targeting of neurodegenerative diseases may require analyses not anchored on current clinicopathologic criteria but instead on biological signals generated from large deeply phenotyped aging populations or from smaller but well-defined genetic-molecular cohorts.