DOPAL derived alpha-synuclein oligomers impair synaptic vesicles physiological function.
DOPAL derived alpha-synuclein oligomers impair synaptic vesicles physiological function.
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DOI：
10.1038/srep40699
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发表时间：
2017-01-13
影响因子：
4.6
通讯作者：
Bubacco L
中科院分区：
文献类型：
--
作者：
Plotegher N;Berti G;Ferrari E;Tessari I;Zanetti M;Lunelli L;Greggio E;Bisaglia M;Veronesi M;Girotto S;Dalla Serra M;Perego C;Casella L;Bubacco L
帕金森病是一种神经退行性疾病，以多巴胺能神经元死亡和存活神经元中α-突触核蛋白(AS)聚集为特征。多巴胺分解代谢物3，4-二羟基苯乙醛(DOPAL)是一种高活性、高毒性的分子，通过对赖氨酸残基进行共价修饰而导致AS齐聚。在这里，我们表明DOPAL诱导的神经元AS寡聚体的形成与突触小泡的损伤和突触小囊泡池的改变有关。为了研究导致突触损伤的分子机制，我们首先旨在表征AS-DOPAL寡聚体的生化和生物物理性质；AS-DOPAL寡聚体是能够渗透含胆固醇的脂膜的不同种类的大分子集合。AS-DOPAL寡聚体可以在突触小泡的体外模型和细胞模型中诱导多巴胺泄漏。在细胞质中转化为DOPAL后释放的多巴胺可能会引发一个有害的循环，进一步推动AS-DOPAL寡聚体的形成，导致神经退化。
Parkinson’s disease is a neurodegenerative disorder characterized by the death of dopaminergic neurons and by accumulation of alpha-synuclein (aS) aggregates in the surviving neurons. The dopamine catabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) is a highly reactive and toxic molecule that leads to aS oligomerization by covalent modifications to lysine residues. Here we show that DOPAL-induced aS oligomer formation in neurons is associated with damage of synaptic vesicles, and with alterations in the synaptic vesicles pools. To investigate the molecular mechanism that leads to synaptic impairment, we first aimed to characterize the biochemical and biophysical properties of the aS-DOPAL oligomers; heterogeneous ensembles of macromolecules able to permeabilise cholesterol-containing lipid membranes. aS-DOPAL oligomers can induce dopamine leak in an in vitro model of synaptic vesicles and in cellular models. The dopamine released, after conversion to DOPAL in the cytoplasm, could trigger a noxious cycle that further fuels the formation of aS-DOPAL oligomers, inducing neurodegeneration.