ArticleActa neuropathologica communications2021
Alpha-synuclein from patient Lewy bodies exhibits distinct pathological activity that can be propagated in vitro.
Article in Acta neuropathologica communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 80 citations in OpenAlex.
- Structure-function relationship of alpha-synuclein fibrillar polymorphs derived from distinct synucleinopathies.Molecular systems biology · 2026Article
- Determination of α-Synuclein Protein Interactions by μMap Photoproximity Labeling.Journal of the American Chemical Society · 2026Article
- Cracking the code of native amyloid fibrils: advances and next steps to enable pathology-informed therapeutic and diagnostic.Nature structural & molecular biology · 2026Review
- Molecular Mechanisms and Therapeutic Potential of Degron-Mediated Proteostasis Regulation in Neurodegenerative Diseases.Cellular and molecular neurobiology · 2026Review
- Seed amplification of MSA alpha-synuclein aggregates preserves the biological and structural properties of brain-derived aggregates.Nature communications · 2025Article
- The Small Molecule DDOX Confers Neuroprotection and Alleviates Motor Deficits in a Preclinical Rat Model of Parkinson's Disease.Neurotoxicity research · 2025Article
- Neurodegeneration as Ecosystem Failure: A New Paradigm for Prevention and Treatment.International journal of molecular sciences · 2025Review
- Interactions of Neurodegenerative Disease Positron Emission Tomography Imaging Probe Candidates with the C-Terminus of α-Synuclein Fibrils.Chembiochem : a European journal of chemical biology · 2025Article
- Determination of α-Synuclein Protein Interactions by μMap Photo-proximity Labeling.bioRxiv : the preprint server for biology · 2025Article
- Differential role of C-terminal truncations on alpha-synuclein pathology and Lewy body formation.NPJ Parkinson's disease · 2025Article
- Investigation of All Disease-Relevant Lysine Acetylation Sites in α-Synuclein Enabled by Non-canonical Amino Acid Mutagenesis.bioRxiv : the preprint server for biology · 2025Article
- Strategic Modulation of Polarity and Viscosity Sensitivity of Bimane Molecular Rotor-Based Fluorophores for Imaging α-Synuclein.Journal of the American Chemical Society · 2025Article
- Oxytetracycline and its Non-Antibiotic Derivative DOT Protect Midbrain Dopamine Neurons from Iron-Driven Oxidative Damage.Neurotoxicity research · 2025Article
- Age-dependent progression from clearance to vulnerability in the early response of periventricular microglia to α-synuclein toxic species.Molecular neurodegeneration · 2025Article
- High-resolution Cryo-EM Structure Determination of a-Synuclein-A Prototypical Amyloid Fibril.Bio-protocol · 2025Article
- Microglia Process α-Synuclein Fibrils and Enhance their Pathogenicity in a TREM2-Dependent Manner.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Subtle concentration changes in zinc hold the key to fibrillation of α-synuclein: an updated insight on the micronutrient's role in prevention of neurodegenerative disorders.Frontiers in molecular biosciences · 2025Review
- Conformation Study and Design of Novel 6-Hydroxybenzothiazole-2- Carboxamides as Potentially Potent and Selective Monoamine Oxidase B Inhibitors for Neuroprotection.Current topics in medicinal chemistry · 2025Article
- 3D-QSAR, design, molecular docking and dynamics simulation studies of novel 6-hydroxybenzothiazole-2-carboxamides as potentially potent and selective monoamine oxidase B inhibitors.Frontiers in pharmacology · 2025Article
- Molecular Symphony of Mitophagy: Ubiquitin-Specific Protease-30 as a Maestro for Precision Management of Neurodegenerative Diseases.CNS neuroscience & therapeutics · 2025Review
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9 authors at 2 institutions in 1 country.
Funding
Abstract
Lewy bodies (LBs) are complex, intracellular inclusions that are common pathological features of many neurodegenerative diseases. They consist largely of aggregated forms of the protein alpha-Synuclein (α-Syn), which misfolds to give rise to beta-sheet rich amyloid fibrils. The aggregation of monomers into fibrils occurs readily in vitro and pre-formed fibrils (PFFs) generated from recombinant α-Syn monomers are the basis of many models of LB diseases. These α-Syn PFFs recapitulate many pathological phenotypes in both cultured cells and animal models including the formation of α-Syn rich, insoluble aggregates, neuron loss, and motor deficits. However, it is not clear how closely α-Syn PFFs recapitulate the biological behavior of LB aggregates isolated directly from patients. Direct interrogation of the cellular response to LB-derived α-Syn has thus far been limited. Here we demonstrate that α-Syn aggregates derived from LB disease patients induce pathology characterized by a prevalence of large somatic inclusions that is distinct from the primarily neuritic pathology induced by α-Syn PFFs in our cultured neuron model. Moreover, these LB-derived aggregates can be amplified in vitro using recombinant α-Syn to generate aggregates that maintain the unique, somatic pathological phenotype of the original material. Amplified LB aggregates also showed greater uptake in cultured neurons and greater pathological burden and more rapid pathological spread in injected mouse brains, compared to α-Syn PFFs. Our work indicates that LB-derived α-Syn from diseased brains represents a distinct conformation species with unique biological activities that has not been previously observed in fully recombinant α-Syn aggregates and demonstrate a new strategy for improving upon α-Syn PFF models of synucleinopathies using amplified LBs.
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