Abstract：
These facts argue against the gain-of-function synucleinopathy hypothesis, which proposes that Lewy pathology causes Parkinson\'s disease: (1) most brains from people without neurological symptoms have multiple pathologies; (2) neither pathology type nor distribution correlate with disease severity or progression in Parkinson\'s disease; (3) aggregated α-synuclein in the form of Lewy bodies is not a space-occupying lesion but the insoluble fraction of its precursor, soluble monomeric α-synuclein; (4) pathology spread is passive, occurring by irreversible nucleation, not active replication; and (5) low cerebrospinal fluid α-synuclein levels predict brain atrophy and clinical disease progression. The transformation of α-synuclein into Lewy pathology may occur as a response to biological, toxic, or infectious stressors whose persistence perpetuates the nucleation process, depleting normal α-synuclein and eventually leading to Parkinson\'s symptoms from neuronal death. We propose testing the loss-of-function synucleinopenia hypothesis by evaluating the clinical and neurodegenerative rescue effect of replenishing the levels of monomeric α-synuclein.
摘要：
这些事实与获得功能的突触核蛋白病假说相反，其中提出路易病理导致帕金森病：（1）大多数来自没有神经症状的人的大脑有多种病理；（2）病理类型和分布与帕金森病的疾病严重程度或进展都不相关；（3）以路易体形式聚集的α-突触核蛋白不是占位性病变，而是其前体的不溶性部分，可溶性单体α-突触核蛋白；(4)病理传播是被动的，通过不可逆成核发生，不活跃的复制;和(5)低脑脊液α-突触核蛋白水平预测脑萎缩和临床疾病进展。α-突触核蛋白转化为路易病理可能是对生物学的反应，有毒,或传染性应激源，其持久性延续了成核过程，消耗正常的α-突触核蛋白并最终导致神经元死亡导致帕金森病症状。我们建议通过评估补充单体α-突触核蛋白水平的临床和神经退行性挽救作用来测试功能丧失突触核蛋白减少假说。
