{"title":"Fibril-seeded animal models of synucleinopathies: Pathological mechanisms, disease modeling, and therapeutic implications.","authors":"Norihito Uemura","doi":"10.1016/j.neures.2025.04.008","DOIUrl":null,"url":null,"abstract":"<p><p>Accumulating evidence suggests that prion-like spread of misfolded α-Synuclein (αSyn) underlies the pathological progression of Lewy body diseases (LBD). Animal models injected with αSyn preformed fibrils (PFFs) have provided strong evidence for the prion hypothesis in LBD. Moreover, αSyn PFFs can be administered to various hosts and regions, contributing to the elucidation of pathological mechanisms and disease modeling. These models have also been used to identify biomarkers and develop new disease-modifying therapies for LBD. In contrast, it remains unknown how the prion-like properties of αSyn contribute to the pathogenesis of multiple system atrophy (MSA). Recent studies indicate that conformationally distinct αSyn fibrils induce different pathological features in animals, supporting the strain hypothesis, which suggests that conformational variations in αSyn fibrils contribute to the clinicopathological heterogeneity in synucleinopathies. However, the study of disease-specific αSyn fibrils in pathological mechanisms and disease modeling is still in its early stages. This review aims to highlight recent advances in αSyn fibril-seeded animal models with an emphasis on their unique features and utility in exploring pathological mechanisms and identifying novel disease-modifying therapies. In addition, I discuss future directions for refining these models in light of the emerging strain hypothesis in synucleinopathies.</p>","PeriodicalId":19146,"journal":{"name":"Neuroscience Research","volume":" ","pages":""},"PeriodicalIF":2.4000,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neuroscience Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.neures.2025.04.008","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
Accumulating evidence suggests that prion-like spread of misfolded α-Synuclein (αSyn) underlies the pathological progression of Lewy body diseases (LBD). Animal models injected with αSyn preformed fibrils (PFFs) have provided strong evidence for the prion hypothesis in LBD. Moreover, αSyn PFFs can be administered to various hosts and regions, contributing to the elucidation of pathological mechanisms and disease modeling. These models have also been used to identify biomarkers and develop new disease-modifying therapies for LBD. In contrast, it remains unknown how the prion-like properties of αSyn contribute to the pathogenesis of multiple system atrophy (MSA). Recent studies indicate that conformationally distinct αSyn fibrils induce different pathological features in animals, supporting the strain hypothesis, which suggests that conformational variations in αSyn fibrils contribute to the clinicopathological heterogeneity in synucleinopathies. However, the study of disease-specific αSyn fibrils in pathological mechanisms and disease modeling is still in its early stages. This review aims to highlight recent advances in αSyn fibril-seeded animal models with an emphasis on their unique features and utility in exploring pathological mechanisms and identifying novel disease-modifying therapies. In addition, I discuss future directions for refining these models in light of the emerging strain hypothesis in synucleinopathies.
期刊介绍:
The international journal publishing original full-length research articles, short communications, technical notes, and reviews on all aspects of neuroscience
Neuroscience Research is an international journal for high quality articles in all branches of neuroscience, from the molecular to the behavioral levels. The journal is published in collaboration with the Japan Neuroscience Society and is open to all contributors in the world.