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
{"title":"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","authors":"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","doi":"10.1126/sciadv.adq3539","DOIUrl":null,"url":null,"abstract":"<div >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.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adq3539","citationCount":"0","resultStr":"{\"title\":\"Mouse α-synuclein fibrils are structurally and functionally distinct from human fibrils associated with Lewy body diseases\",\"authors\":\"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\",\"doi\":\"10.1126/sciadv.adq3539\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div >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.</div>\",\"PeriodicalId\":21609,\"journal\":{\"name\":\"Science Advances\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":11.7000,\"publicationDate\":\"2024-11-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.science.org/doi/reader/10.1126/sciadv.adq3539\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Science Advances\",\"FirstCategoryId\":\"103\",\"ListUrlMain\":\"https://www.science.org/doi/10.1126/sciadv.adq3539\",\"RegionNum\":1,\"RegionCategory\":\"综合性期刊\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MULTIDISCIPLINARY SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Advances","FirstCategoryId":"103","ListUrlMain":"https://www.science.org/doi/10.1126/sciadv.adq3539","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
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.
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.