Raphaella W. L. So, Genki Amano, Erica Stuart, Aeen Ebrahim Amini, Adriano Aguzzi, Graham L. Collingridge, Joel C. Watts
{"title":"在转基因突触核蛋白病小鼠模型中,α-突触核蛋白菌株的传播与细胞朊病毒蛋白的表达无关","authors":"Raphaella W. L. So, Genki Amano, Erica Stuart, Aeen Ebrahim Amini, Adriano Aguzzi, Graham L. Collingridge, Joel C. Watts","doi":"10.1371/journal.ppat.1012517","DOIUrl":null,"url":null,"abstract":"The cellular prion protein, PrP<jats:sup>C</jats:sup>, has been postulated to function as a receptor for α-synuclein, potentially facilitating cell-to-cell spreading and/or toxicity of α-synuclein aggregates in neurodegenerative disorders such as Parkinson’s disease. Previously, we generated the “Salt (S)” and “No Salt (NS)” strains of α-synuclein aggregates that cause distinct pathological phenotypes in M83 transgenic mice overexpressing A53T-mutant human α-synuclein. To test the hypothesis that PrP<jats:sup>C</jats:sup> facilitates the propagation of α-synuclein aggregates, we produced M83 mice that either express or do not express PrP<jats:sup>C</jats:sup>. Following intracerebral inoculation with the S or NS strain, the absence of PrP<jats:sup>C</jats:sup> in M83 mice did not prevent disease development and had minimal influence on α-synuclein strain-specified attributes such as the extent of cerebral α-synuclein deposition, selective targeting of specific brain regions and cell types, the morphology of induced α-synuclein deposits, and the structural fingerprints of protease-resistant α-synuclein aggregates. Likewise, there were no appreciable differences in disease manifestation between PrP<jats:sup>C</jats:sup>-expressing and PrP<jats:sup>C</jats:sup>-lacking M83 mice following intraperitoneal inoculation of the S strain. Interestingly, intraperitoneal inoculation with the NS strain resulted in two distinct disease phenotypes, indicative of α-synuclein strain evolution, but this was also independent of PrP<jats:sup>C</jats:sup> expression. Overall, these results suggest that PrP<jats:sup>C</jats:sup> plays at most a minor role in the propagation, neuroinvasion, and evolution of α-synuclein strains in mice that express A53T-mutant human α-synuclein. Thus, other putative receptors or cell-to-cell propagation mechanisms may have a larger effect on the spread of α-synuclein aggregates during disease.","PeriodicalId":20178,"journal":{"name":"PLoS Pathogens","volume":null,"pages":null},"PeriodicalIF":6.7000,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"α-Synuclein strain propagation is independent of cellular prion protein expression in a transgenic synucleinopathy mouse model\",\"authors\":\"Raphaella W. L. So, Genki Amano, Erica Stuart, Aeen Ebrahim Amini, Adriano Aguzzi, Graham L. Collingridge, Joel C. Watts\",\"doi\":\"10.1371/journal.ppat.1012517\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"The cellular prion protein, PrP<jats:sup>C</jats:sup>, has been postulated to function as a receptor for α-synuclein, potentially facilitating cell-to-cell spreading and/or toxicity of α-synuclein aggregates in neurodegenerative disorders such as Parkinson’s disease. Previously, we generated the “Salt (S)” and “No Salt (NS)” strains of α-synuclein aggregates that cause distinct pathological phenotypes in M83 transgenic mice overexpressing A53T-mutant human α-synuclein. To test the hypothesis that PrP<jats:sup>C</jats:sup> facilitates the propagation of α-synuclein aggregates, we produced M83 mice that either express or do not express PrP<jats:sup>C</jats:sup>. Following intracerebral inoculation with the S or NS strain, the absence of PrP<jats:sup>C</jats:sup> in M83 mice did not prevent disease development and had minimal influence on α-synuclein strain-specified attributes such as the extent of cerebral α-synuclein deposition, selective targeting of specific brain regions and cell types, the morphology of induced α-synuclein deposits, and the structural fingerprints of protease-resistant α-synuclein aggregates. Likewise, there were no appreciable differences in disease manifestation between PrP<jats:sup>C</jats:sup>-expressing and PrP<jats:sup>C</jats:sup>-lacking M83 mice following intraperitoneal inoculation of the S strain. Interestingly, intraperitoneal inoculation with the NS strain resulted in two distinct disease phenotypes, indicative of α-synuclein strain evolution, but this was also independent of PrP<jats:sup>C</jats:sup> expression. Overall, these results suggest that PrP<jats:sup>C</jats:sup> plays at most a minor role in the propagation, neuroinvasion, and evolution of α-synuclein strains in mice that express A53T-mutant human α-synuclein. Thus, other putative receptors or cell-to-cell propagation mechanisms may have a larger effect on the spread of α-synuclein aggregates during disease.\",\"PeriodicalId\":20178,\"journal\":{\"name\":\"PLoS Pathogens\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.7000,\"publicationDate\":\"2024-09-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"PLoS Pathogens\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1371/journal.ppat.1012517\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"Immunology and Microbiology\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"PLoS Pathogens","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1371/journal.ppat.1012517","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Immunology and Microbiology","Score":null,"Total":0}
α-Synuclein strain propagation is independent of cellular prion protein expression in a transgenic synucleinopathy mouse model
The cellular prion protein, PrPC, has been postulated to function as a receptor for α-synuclein, potentially facilitating cell-to-cell spreading and/or toxicity of α-synuclein aggregates in neurodegenerative disorders such as Parkinson’s disease. Previously, we generated the “Salt (S)” and “No Salt (NS)” strains of α-synuclein aggregates that cause distinct pathological phenotypes in M83 transgenic mice overexpressing A53T-mutant human α-synuclein. To test the hypothesis that PrPC facilitates the propagation of α-synuclein aggregates, we produced M83 mice that either express or do not express PrPC. Following intracerebral inoculation with the S or NS strain, the absence of PrPC in M83 mice did not prevent disease development and had minimal influence on α-synuclein strain-specified attributes such as the extent of cerebral α-synuclein deposition, selective targeting of specific brain regions and cell types, the morphology of induced α-synuclein deposits, and the structural fingerprints of protease-resistant α-synuclein aggregates. Likewise, there were no appreciable differences in disease manifestation between PrPC-expressing and PrPC-lacking M83 mice following intraperitoneal inoculation of the S strain. Interestingly, intraperitoneal inoculation with the NS strain resulted in two distinct disease phenotypes, indicative of α-synuclein strain evolution, but this was also independent of PrPC expression. Overall, these results suggest that PrPC plays at most a minor role in the propagation, neuroinvasion, and evolution of α-synuclein strains in mice that express A53T-mutant human α-synuclein. Thus, other putative receptors or cell-to-cell propagation mechanisms may have a larger effect on the spread of α-synuclein aggregates during disease.
期刊介绍:
Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.