ArticleJournal of Parkinson's disease2024
Structurally targeted mutagenesis identifies key residues supporting α-synuclein misfolding in multiple system atrophy.
Article in Journal of Parkinson's disease, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
What it found
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Who cites it
9 citing papers in PubMed.
- Adaptation of α-synuclein fibrils following multiple system atrophy transmission to mice.bioRxiv : the preprint server for biology · 2026Article
- The Progress of Active Immunotherapy for Parkinson's Disease.International journal of molecular sciences · 2026Review
- Co-infection with two α-synuclein strains reveals novel synergistic interactions.Acta neuropathologica · 2025Article
- Tauopathy strains differentially replicate in vitro in the presence of mutant tau monomer.Neurobiology of disease · 2025Article
- Co-infection with two α-synuclein strains reveals novel synergistic interactions.bioRxiv : the preprint server for biology · 2025Article
- Evidence of a novel α-synuclein strain isolated from a Parkinson's disease with dementia patient sample.Acta neuropathologica communications · 2025Article
- Limitations and Applications of Rodent Models in Tauopathy and Synucleinopathy Research.Journal of neurochemistry · 2025Review
- Review
- A-synuclein prion strains differentially adapt after passage in mice.PLoS pathogens · 2024Article
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Authors and funding
8 authors.
Funding
Abstract
backgroundMultiple system atrophy (MSA) and Parkinson's disease (PD) are caused by misfolded α-synuclein spreading throughout the central nervous system. While familial PD is linked to several α-synuclein mutations, no mutations are associated with MSA. We previously showed that the familial PD mutation E46K inhibits replication of MSA prions both
objectiveHere we sought to further interrogate α-synuclein misfolding to identify the structural determinants that contribute to MSA strain biology.
methodsWe engineered a panel of cell lines harbouring both PD-linked and novel mutations designed to identify key residues that facilitate α-synuclein misfolding in MSA. We also used Maestro
resultsIn many cases, our modelling accurately identified mutations that facilitated or inhibited MSA replication. However, Maestro was occasionally unable to predict the effect of a mutation, demonstrating the challenge of using computational tools to investigate intrinsically disordered proteins. Finally, we used our cellular models to determine the mechanism underlying the E46K-driven inhibition of MSA replication, finding that the E46/K80 salt bridge is necessary to support α-synuclein misfolding.
conclusionsOur studies used a structure-based approach to investigate α-synuclein misfolding, resulting in the creation of a powerful panel of cell lines that can be used to interrogate MSA strain biology.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.