小鼠α-突触核蛋白纤维在结构上和功能上有别于与路易体疾病相关的人类纤维

IF 11.7 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Science Advances Pub Date : 2024-11-01 DOI:10.1126/sciadv.adq3539
Arpine Sokratian, Ye Zhou, Meltem Tatli, Kevin J. Burbidge, Enquan Xu, Elizabeth Viverette, Sonia Donzelli, Addison M. Duda, Yuan Yuan, Huizhong Li, Samuel Strader, Nirali Patel, Lauren Shiell, Tuyana Malankhanova, Olivia Chen, Joseph R. Mazzulli, Lalith Perera, Henning Stahlberg, Mario Borgnia, Alberto Bartesaghi, Hilal A. Lashuel, Andrew B. West
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引用次数: 0

摘要

α-突触核蛋白聚集和纤维化的复杂过程在帕金森病(PD)和多系统萎缩(MSA)中起着关键作用。虽然小鼠α-突触核蛋白能在体外纤化,但研究中常用来诱导这一过程或形成的这些纤丝能否再现人脑中的结构仍是未知数。在这里,我们首次报告了小鼠α-突触核蛋白纤维的原子结构。该结构与MSA扩增和PD相关的E46K纤维有惊人的相似性。然而,小鼠α-突触核蛋白纤维的堆积排列发生了改变,疏水性降低,碎裂敏感性提高,只能引起微弱的免疫反应。此外,小鼠α-突触核蛋白纤维在神经元和人源化α-突触核蛋白小鼠中的病理扩散加剧。这些发现提供了对α-突触核蛋白致病性结构基础的重要见解,并强调了在开发相关诊断探针和治疗干预措施时重新评估小鼠α-突触核蛋白纤维作用的必要性。
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Mouse α-synuclein fibrils are structurally and functionally distinct from human fibrils associated with Lewy body diseases
The intricate process of α-synuclein aggregation and fibrillization holds pivotal roles in Parkinson’s disease (PD) and multiple system atrophy (MSA). While mouse α-synuclein can fibrillize in vitro, whether these fibrils commonly used in research to induce this process or form can reproduce structures in the human brain remains unknown. Here, we report the first atomic structure of mouse α-synuclein fibrils, which was solved in parallel by two independent teams. The structure shows striking similarity to MSA-amplified and PD-associated E46K fibrils. However, mouse α-synuclein fibrils display altered packing arrangements, reduced hydrophobicity, and heightened fragmentation sensitivity and evoke only weak immunological responses. Furthermore, mouse α-synuclein fibrils exhibit exacerbated pathological spread in neurons and humanized α-synuclein mice. These findings provide critical insights into the structural underpinnings of α-synuclein pathogenicity and emphasize a need to reassess the role of mouse α-synuclein fibrils in the development of related diagnostic probes and therapeutic interventions.
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来源期刊
Science Advances
Science Advances 综合性期刊-综合性期刊
CiteScore
21.40
自引率
1.50%
发文量
1937
审稿时长
29 weeks
期刊介绍: Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.
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