DOPAL initiates αSynuclein-dependent impaired proteostasis and degeneration of neuronal projections in Parkinson's disease.
DOPAL initiates αSynuclein-dependent impaired proteostasis and degeneration of neuronal projections in Parkinson's disease.
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DOI：
10.1038/s41531-023-00485-1
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发表时间：
2023-03-25
影响因子：
8.7
通讯作者：
Bubacco, Luigi
中科院分区：
文献类型：
--
作者：
Masato, Anna;Plotegher, Nicoletta;Terrin, Francesca;Sandre, Michele;Faustini, Gaia;Thor, Andrea;Adams, Stephen;Berti, Giulia;Cogo, Susanna;De Lazzari, Federica;Fontana, Camilla Maria;Martinez, Paul Anthony;Strong, Randy;Bandopadhyay, Rina;Bisaglia, Marco;Bellucci, Arianna;Greggio, Elisa;Dalla Valle, Luisa;Boassa, Daniela;Bubacco, Luigi
多巴胺稳态失调已被认为是帕金森病（PD）中黑质纹状体神经元变性的决定因素之一。在实验模型以及帕金森病患者尸检中的多项研究强调，多巴胺代谢产物3,4 - 二羟基苯乙醛（DOPAL）水平升高，它对蛋白质具有高度反应性。研究表明，DOPAL会共价修饰突触前蛋白α - 突触核蛋白（αSyn），其错误折叠和聚集是帕金森病病理的一个主要特征，会引发多巴胺能神经元中αSyn寡聚化。在此，我们证明了DOPAL会引起原代神经元中αSyn的积累并阻碍αSyn的清除。DOPAL诱导的αSyn积累会降低神经元的恢复能力，损害突触完整性，并使神经突中的蛋白质质量控制途径不堪重负。神经元稳态的逐渐下降进一步导致多巴胺能神经元丢失和运动障碍，正如在体内模型中所显示的那样。最后，我们开发了一种特异性抗体，它检测到特发性帕金森病患者的人类纹状体组织中DOPAL修饰的αSyn增加，证实了αSyn - DOPAL相互作用在帕金森病神经变性中的转化相关性。
Dopamine dyshomeostasis has been acknowledged among the determinants of nigrostriatal neuron degeneration in Parkinson’s disease (PD). Several studies in experimental models and postmortem PD patients underlined increasing levels of the dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is highly reactive towards proteins. DOPAL has been shown to covalently modify the presynaptic protein αSynuclein (αSyn), whose misfolding and aggregation represent a major trait of PD pathology, triggering αSyn oligomerization in dopaminergic neurons. Here, we demonstrated that DOPAL elicits αSyn accumulation and hampers αSyn clearance in primary neurons. DOPAL-induced αSyn buildup lessens neuronal resilience, compromises synaptic integrity, and overwhelms protein quality control pathways in neurites. The progressive decline of neuronal homeostasis further leads to dopaminergic neuron loss and motor impairment, as showed in in vivo models. Finally, we developed a specific antibody which detected increased DOPAL-modified αSyn in human striatal tissues from idiopathic PD patients, corroborating the translational relevance of αSyn-DOPAL interplay in PD neurodegeneration.
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影响因子：
4.1
作者：
Fan, Hui-Hui;Zheng, Jing;Huang, Xiao-Ya;Wu, Ke-Yun;Cui, Lei;Dong, Hao-Jia;Wang, Zhen;Zhang, Xiong;Zhu, Jian-Hong
通讯作者：
Zhu, Jian-Hong
影响因子：
15.1
作者：
Danzer KM;Kranich LR;Ruf WP;Cagsal-Getkin O;Winslow AR;Zhu L;Vanderburg CR;McLean PJ
通讯作者：
McLean PJ
影响因子：
25
作者：
Graves, Steven M.;Xie, Zhong;Surmeier, D. James
通讯作者：
Surmeier, D. James
影响因子：
64.8
作者：
FELLMAN, JH
通讯作者：
FELLMAN, JH
影响因子：
56.9
作者：
Conway, KA;Rochet, JC;Lansbury, PT
通讯作者：
Lansbury, PT