Neurosearch Center, 76 Henry Street, Toronto, ON, M5T1X2, Canada.
Biomed Pharmacother. 2016 Oct;83:412-430. doi: 10.1016/j.biopha.2016.06.042. Epub 2016 Jul 15.
Neurodegenerative disorders are highly heterogeneous for the locations affected and the nature of the aggregated proteins. Nearly 80% of the neurodegenerative disorders occur sporadically, indicating that certain factors must combine to initiate the degenerative changes. The contiguous extension of degenerative changes from cell to cell, the association with viral fusion proteins, loss of dendritic spines (postsynaptic terminals), and the eventual degeneration of cells indicate the presence of a unique mechanism for inter-cellular spread of pathology. It is not known whether the "loss of function" states of the still unknown normal nervous system operations can lead to neurodegenerative disorders. Here, the possible loss of function states of a proposed normal nervous system function are examined. A reversible inter-postsynaptic functional LINK (IPL) mechanism, consisting of transient inter-postsynaptic membrane (IPM) hydration exclusion and partial to complete IPM hemifusions, was proposed as a critical step necessary for the binding process and the induction of internal sensations of higher brain functions. When various findings from different neurodegenerative disorders are systematically organized and examined, disease features match the effects of loss of function states of different IPLs. Changes in membrane composition, enlargement of dendritic spines by dopamine and viral fusion proteins are capable of altering the IPLs to form IPM fusion. The latter can lead to the observed lateral spread of pathology, inter-neuronal cytoplasmic content mixing and abnormal protein aggregation. Since both the normal mechanism of reversible IPM hydration exclusion and the pathological process of transient IPM fusion can evade detection, testing their occurrence may provide preventive and therapeutic opportunities for these disorders.
神经退行性疾病在受影响的部位和聚集蛋白的性质上高度异质。近 80%的神经退行性疾病是散发性的，这表明某些因素必须结合起来启动退行性变化。退行性变化从一个细胞连续扩展到另一个细胞，与病毒融合蛋白的关联，树突棘（突触后末端）的丧失，以及细胞的最终退化，表明存在一种独特的机制，可以在细胞间传播病理学。目前尚不清楚仍未知的正常神经系统功能的“功能丧失”状态是否会导致神经退行性疾病。在这里，检查了所提出的正常神经系统功能的可能的功能丧失状态。一个可逆的突触间功能性 LINK（IPL）机制，由短暂的突触间膜（IPM）水合排除和部分到完全的 IPM 半融合组成，被提议作为绑定过程和诱导大脑高级功能的内部感觉的必要关键步骤。当从不同的神经退行性疾病中得到的各种发现被系统地组织和检查时，疾病特征与不同 IPL 的功能丧失状态的影响相匹配。膜成分的变化，多巴胺和病毒融合蛋白对树突棘的增大，能够改变 IPL 以形成 IPM 融合。后者可导致观察到的病理学横向扩散、神经元间细胞质内容物混合和异常蛋白聚集。由于可逆的 IPM 水合排除的正常机制和短暂的 IPM 融合的病理过程都可能逃避检测，因此检测它们的发生可能为这些疾病提供预防和治疗的机会。
