Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
Acta Neuropathol Commun. 2018 May 1;6(1):35. doi: 10.1186/s40478-018-0537-x.
Neuronal inclusions composed of α-synuclein (α-syn) characterize Parkinson's Disease (PD) and Dementia with Lewy bodies (DLB). Cognitive dysfunction defines DLB, and up to 80% of PD patients develop dementia. α-Syn inclusions are abundant in the hippocampus, yet functional consequences are unclear. To determine if pathologic α-syn causes neuronal defects, we induced endogenous α-syn to form inclusions resembling those found in diseased brains by treating hippocampal neurons with α-syn fibrils. At seven days after adding fibrils, α-syn inclusions are abundant in axons, but there is no cell death at this time point, allowing us to assess for potential alterations in neuronal function that are not caused by neuron death. We found that exposure of neurons to fibrils caused a significant reduction in mushroom spine densities, adding to the growing body of literature showing that altered spine morphology is a major pathologic phenotype in synucleinopathies. The reduction in spine densities occurred only in wild type neurons and not in neurons from α-syn knockout mice, suggesting that the changes in spine morphology result from fibril-induced corruption of endogenously expressed α-syn. Paradoxically, reduced postsynaptic spine density was accompanied by increased frequency of miniature excitatory postsynaptic currents (EPSCs) and presynaptic docked vesicles, suggesting enhanced presynaptic function. Action-potential dependent activity was unchanged, suggesting compensatory mechanisms responding to synaptic defects. Although activity at the level of the synapse was unchanged, neurons exposed to α-syn fibrils, showed reduced frequency and amplitudes of spontaneous Ca transients. These findings open areas of research to determine the mechanisms that alter neuronal function in brain regions critical for cognition at time points before neuron death.
由α-突触核蛋白 (α-syn) 组成的神经元包含物是帕金森病 (PD) 和路易体痴呆 (DLB) 的特征。认知功能障碍定义了 DLB，高达 80%的 PD 患者会发展为痴呆。α-syn 包含物在海马体中大量存在，但功能后果尚不清楚。为了确定病理性 α-syn 是否导致神经元缺陷，我们通过用 α-syn 纤维处理海马神经元，诱导内源性 α-syn 形成类似于在患病大脑中发现的包含物。在添加纤维后的第 7 天，α-syn 包含物在轴突中大量存在，但此时没有细胞死亡，这使我们能够评估潜在的神经元功能改变，而这些改变不是由神经元死亡引起的。我们发现，神经元暴露于纤维中会导致蘑菇状棘突密度显著降低，这增加了越来越多的文献表明，改变的棘突形态是突触核蛋白病的主要病理表型。棘突密度的降低仅发生在野生型神经元中，而不在 α-syn 敲除小鼠的神经元中，这表明棘突形态的变化是由纤维诱导的内源性表达的 α-syn 腐败引起的。矛盾的是，突触后棘突密度的降低伴随着兴奋性突触后电流 (EPSC) 和突触前停靠囊泡的频率增加，表明突触前功能增强。动作电位依赖性活动没有变化，表明存在补偿机制来应对突触缺陷。尽管突触水平的活动没有变化，但暴露于 α-syn 纤维的神经元显示自发 Ca 瞬变的频率和幅度降低。这些发现为确定在神经元死亡之前的时间点改变对认知至关重要的脑区神经元功能的机制开辟了研究领域。
