Mutations in human prion-like domains: pathogenic but not always amyloidogenic
Heterogeneous nuclear ribonucleoproteins (hnRNPs) are multifunctional proteins with integral roles in RNA metabolism and the regulation of alternative splicing. These proteins typically contain prion-like domains of low complexity (PrLDs or LCDs) that govern their assembly into either functional or...
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Taylor & Francis Group
2024-12-01
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| Series: | Prion |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19336896.2024.2329186 |
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| author | Andrea Bartolomé-Nafría Javier García-Pardo Salvador Ventura |
| author_facet | Andrea Bartolomé-Nafría Javier García-Pardo Salvador Ventura |
| author_sort | Andrea Bartolomé-Nafría |
| collection | DOAJ |
| description | Heterogeneous nuclear ribonucleoproteins (hnRNPs) are multifunctional proteins with integral roles in RNA metabolism and the regulation of alternative splicing. These proteins typically contain prion-like domains of low complexity (PrLDs or LCDs) that govern their assembly into either functional or pathological amyloid fibrils. To date, over 60 mutations targeting the LCDs of hnRNPs have been identified and associated with a spectrum of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer’s disease (AD). The cryo-EM structures of pathological and functional fibrils formed by different hnRNPs have been recently elucidated, including those of hnRNPA1, hnRNPA2, hnRNPDL-2, TDP-43, and FUS. In this review, we discuss the structural features of these amyloid assemblies, placing particular emphasis on scrutinizing the impact of prevalent disease-associated mutations mapping within their LCDs. By performing systematic energy calculations, we reveal a prevailing trend of destabilizing effects induced by these mutations in the amyloid structure, challenging the traditionally assumed correlation between pathogenicity and amyloidogenic propensity. Understanding the molecular basis of this discrepancy might provide insights for developing targeted therapeutic strategies to combat hnRNP-associated diseases. |
| format | Article |
| id | doaj-art-5a296812dab845b192abfe0a4c9b32c0 |
| institution | Kabale University |
| issn | 1933-6896 1933-690X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
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| series | Prion |
| spelling | doaj-art-5a296812dab845b192abfe0a4c9b32c02025-02-05T12:40:51ZengTaylor & Francis GroupPrion1933-68961933-690X2024-12-01181283910.1080/19336896.2024.2329186Mutations in human prion-like domains: pathogenic but not always amyloidogenicAndrea Bartolomé-Nafría0Javier García-Pardo1Salvador Ventura2Institut de Biotecnologia i de Biomedicina (IBB) and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, SpainInstitut de Biotecnologia i de Biomedicina (IBB) and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, SpainInstitut de Biotecnologia i de Biomedicina (IBB) and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, SpainHeterogeneous nuclear ribonucleoproteins (hnRNPs) are multifunctional proteins with integral roles in RNA metabolism and the regulation of alternative splicing. These proteins typically contain prion-like domains of low complexity (PrLDs or LCDs) that govern their assembly into either functional or pathological amyloid fibrils. To date, over 60 mutations targeting the LCDs of hnRNPs have been identified and associated with a spectrum of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer’s disease (AD). The cryo-EM structures of pathological and functional fibrils formed by different hnRNPs have been recently elucidated, including those of hnRNPA1, hnRNPA2, hnRNPDL-2, TDP-43, and FUS. In this review, we discuss the structural features of these amyloid assemblies, placing particular emphasis on scrutinizing the impact of prevalent disease-associated mutations mapping within their LCDs. By performing systematic energy calculations, we reveal a prevailing trend of destabilizing effects induced by these mutations in the amyloid structure, challenging the traditionally assumed correlation between pathogenicity and amyloidogenic propensity. Understanding the molecular basis of this discrepancy might provide insights for developing targeted therapeutic strategies to combat hnRNP-associated diseases.https://www.tandfonline.com/doi/10.1080/19336896.2024.2329186AmyloidCryo-EM structurefunctional amyloidslow complexity domainNeurodegenerationRibonucleoprotein |
| spellingShingle | Andrea Bartolomé-Nafría Javier García-Pardo Salvador Ventura Mutations in human prion-like domains: pathogenic but not always amyloidogenic Prion Amyloid Cryo-EM structure functional amyloids low complexity domain Neurodegeneration Ribonucleoprotein |
| title | Mutations in human prion-like domains: pathogenic but not always amyloidogenic |
| title_full | Mutations in human prion-like domains: pathogenic but not always amyloidogenic |
| title_fullStr | Mutations in human prion-like domains: pathogenic but not always amyloidogenic |
| title_full_unstemmed | Mutations in human prion-like domains: pathogenic but not always amyloidogenic |
| title_short | Mutations in human prion-like domains: pathogenic but not always amyloidogenic |
| title_sort | mutations in human prion like domains pathogenic but not always amyloidogenic |
| topic | Amyloid Cryo-EM structure functional amyloids low complexity domain Neurodegeneration Ribonucleoprotein |
| url | https://www.tandfonline.com/doi/10.1080/19336896.2024.2329186 |
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