Polymorphic Alpha-Synuclein Oligomers: Characterization and Differential Detection with Novel Corresponding Antibodies.
Polymorphic Alpha-Synuclein Oligomers: Characterization and Differential Detection with Novel Corresponding Antibodies.
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DOI：
10.1007/s12035-023-03211-3
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发表时间：
2023-05
影响因子：
5.1
通讯作者：
Kayed, Rakez
中科院分区：
文献类型：
--
作者：
Moore, Kenya;Sengupta, Urmi;Puangmalai, Nicha;Bhatt, Nemil;Kayed, Rakez
许多神经退行性疾病的病理标志是特征性蛋白质聚集体的积累。帕金森病和路易体痴呆可表征为由于蛋白质α-突触核蛋白（α-Syn）的异常积累而引起的突触核蛋白病。研究表明，淀粉样蛋白如α-Syn和tau可以以多态性聚集体的形式存在，这一理论主要在其纤维形态方面得到广泛研究。现在很好地理解，聚集体的中间状态，低聚物，是毒性最大的物质。我们已经证明，当α-Syn被不同的生理诱导剂修饰时，会导致α-Syn的不同寡聚体构象。多态性α-Syn寡聚体表现出不同的性质，如聚集体大小、构象，并与tau差异性相互作用。在这项研究中，我们进一步使用内部新型α-Syn毒性构象单克隆抗体（SynTC）确认α-Syn寡聚多晶型物。α-Syn寡聚多态性的生物学相关性尚不清楚。利用生物化学、生物物理学和基于细胞的测定的组合，我们表征α-Syn寡聚多晶型物。我们发现α-Syn寡聚体多晶型物表现出不同的免疫反应性，SynTC对α-Syn种类表现出不同的选择性和结合亲和力。等温滴定量热实验表明不同的α-Syn：SynTC结合蛋白以种属特异性方式存在。此外，我们发现SynTC以多态性特异性方式差异性地降低α-Syn寡聚多态性介导的神经毒性和原代皮层神经元中的增殖。这些研究证明了多态性α-Syn寡聚体的生物学意义沿着靶向毒性α-Syn聚集体的多态性特异性抗体的重要性。能够靶向α-Syn寡聚物种类的构象异质性并降低其介导的毒性的单克隆抗体具有有希望的免疫学潜力。在线版本包含补充材料，可通过10.1007/s12035-023-03211-3获得。
The pathological hallmark of many neurodegenerative diseases is the accumulation of characteristic proteinaceous aggregates. Parkinson’s disease and dementia with Lewy bodies can be characterized as synucleinopathies due to the abnormal accumulation of the protein alpha-synuclein (α-Syn). Studies have shown amyloidogenic proteins such as α-Syn and tau can exist as polymorphic aggregates, a theory widely studied mostly in their fibrillar morphology. It is now well understood that an intermediate state of aggregates, oligomers, are the most toxic species. We have shown α-Syn, when modified by different physiological inducers, result in distinct oligomeric conformations of α-Syn. Polymorphic α-Syn oligomers exhibit distinct properties such as aggregate size, conformation, and differentially interact with tau. In this study, we confirm α-Syn oligomeric polymorphs furthermore using in-house novel α-Syn toxic conformation monoclonal antibodies (SynTCs). It is unclear the biological relevance of α-Syn oligomeric polymorphisms. Utilizing a combination of biochemical, biophysical, and cell-based assays, we characterize α-Syn oligomeric polymorphs. We found α-Syn oligomeric polymorphs exhibit distinct immunoreactivity and SynTCs exhibit differential selectivity and binding affinity for α-Syn species. Isothermal titration calorimetry experiments suggest distinct α-Syn:SynTC binding enthalpies in a species-specific manner. Additionally, we found SynTCs differentially reduce α-Syn oligomeric polymorph-mediated neurotoxicity and propagation in primary cortical neurons in a polymorph-specific manner. These studies demonstrate the biological significance of polymorphic α-Syn oligomers along with the importance of polymorph-specific antibodies that target toxic α-Syn aggregates. Monoclonal antibodies that can target the conformational heterogeneity of α-Syn oligomeric species and reduce their mediated toxicity have promising immunotherapeutic potential. The online version contains supplementary material available at 10.1007/s12035-023-03211-3.
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影响因子：
3.7
作者：
Fecchio, Chiara;De Franceschi, Giorgia;de Laureto, Patrizia Polverino
通讯作者：
de Laureto, Patrizia Polverino
α-突触核蛋白寡聚物在帕金森病中的作用。
影响因子：
5.6
作者：
Du XY;Xie XX;Liu RT
通讯作者：
Liu RT
影响因子：
16.6
作者：
Cascella R;Chen SW;Bigi A;Camino JD;Xu CK;Dobson CM;Chiti F;Cremades N;Cecchi C
通讯作者：
Cecchi C
影响因子：
10.6
作者：
Castillo-Carranza DL;Guerrero-Muñoz MJ;Sengupta U;Gerson JE;Kayed R
通讯作者：
Kayed R
影响因子：
5.3
作者：
Bonito-Oliva, Alessandra;Schedin-Weiss, Sophia;Graham, W. Vallen
通讯作者：
Graham, W. Vallen