Recursive seed amplification detects distinct α-synuclein strains in cerebrospinal fluid of patients with Parkinson’s disease
Abstract Parkinson’s disease (PD) is a heterogeneous neurodegenerative disorder with a wide range of clinical phenotypes. Pathologically, it is characterized by neuronal inclusions containing misfolded, fibrillar alpha-synuclein (aSyn). Prion-like properties of aSyn contribute to the spread of aSyn...
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BMC
2025-01-01
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| Series: | Acta Neuropathologica Communications |
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| Online Access: | https://doi.org/10.1186/s40478-024-01923-8 |
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| author | Stefan Bräuer Iñaki Schniewind Elisabeth Dinter Björn H. Falkenburger |
| author_facet | Stefan Bräuer Iñaki Schniewind Elisabeth Dinter Björn H. Falkenburger |
| author_sort | Stefan Bräuer |
| collection | DOAJ |
| description | Abstract Parkinson’s disease (PD) is a heterogeneous neurodegenerative disorder with a wide range of clinical phenotypes. Pathologically, it is characterized by neuronal inclusions containing misfolded, fibrillar alpha-synuclein (aSyn). Prion-like properties of aSyn contribute to the spread of aSyn pathology throughout the nervous system as the disease progresses. Utilizing these properties, seed amplification assays (SAA) enable the detection of aSyn pathology in living patients. We hypothesized that structurally distinct aSyn aggregates, or strains, may underlie the clinical heterogeneity of PD. To test this hypothesis, we recursively amplified aSyn fibrils from the cerebrospinal fluid (CSF) of 54 patients (34 people with PD and 20 controls). These fibrils were then characterized regarding SAA kinetic properties and detergent resistance. In addition, cultured cells were transfected with SAA products, and the extent of seeded aSyn pathology was quantified by staining for phosphorylated aSyn followed by automated high-throughput microscopy and image analysis. We found that fibrils, amplified from CSF by recursive SAA, exhibit two types of distinct biophysical properties and have different seeding capacities in cells. These properties are associated with clinical parameters and may therefore help explain the clinical heterogeneity in PD. Measuring aSyn strains may be relevant for prognosis and for therapies targeting aSyn pathology. |
| format | Article |
| id | doaj-art-dd0007f9800a46ff84527bbb23450a27 |
| institution | Kabale University |
| issn | 2051-5960 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj-art-dd0007f9800a46ff84527bbb23450a272025-01-26T12:57:20ZengBMCActa Neuropathologica Communications2051-59602025-01-0113111810.1186/s40478-024-01923-8Recursive seed amplification detects distinct α-synuclein strains in cerebrospinal fluid of patients with Parkinson’s diseaseStefan Bräuer0Iñaki Schniewind1Elisabeth Dinter2Björn H. Falkenburger3Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität DresdenDepartment of Neurology, University Hospital Carl Gustav Carus, Technische Universität DresdenDepartment of Neurology, University Hospital Carl Gustav Carus, Technische Universität DresdenDepartment of Neurology, University Hospital Carl Gustav Carus, Technische Universität DresdenAbstract Parkinson’s disease (PD) is a heterogeneous neurodegenerative disorder with a wide range of clinical phenotypes. Pathologically, it is characterized by neuronal inclusions containing misfolded, fibrillar alpha-synuclein (aSyn). Prion-like properties of aSyn contribute to the spread of aSyn pathology throughout the nervous system as the disease progresses. Utilizing these properties, seed amplification assays (SAA) enable the detection of aSyn pathology in living patients. We hypothesized that structurally distinct aSyn aggregates, or strains, may underlie the clinical heterogeneity of PD. To test this hypothesis, we recursively amplified aSyn fibrils from the cerebrospinal fluid (CSF) of 54 patients (34 people with PD and 20 controls). These fibrils were then characterized regarding SAA kinetic properties and detergent resistance. In addition, cultured cells were transfected with SAA products, and the extent of seeded aSyn pathology was quantified by staining for phosphorylated aSyn followed by automated high-throughput microscopy and image analysis. We found that fibrils, amplified from CSF by recursive SAA, exhibit two types of distinct biophysical properties and have different seeding capacities in cells. These properties are associated with clinical parameters and may therefore help explain the clinical heterogeneity in PD. Measuring aSyn strains may be relevant for prognosis and for therapies targeting aSyn pathology.https://doi.org/10.1186/s40478-024-01923-8Seed amplification assayParkinson’s diseaseStrainsRT-QuICAlpha-synuclein |
| spellingShingle | Stefan Bräuer Iñaki Schniewind Elisabeth Dinter Björn H. Falkenburger Recursive seed amplification detects distinct α-synuclein strains in cerebrospinal fluid of patients with Parkinson’s disease Acta Neuropathologica Communications Seed amplification assay Parkinson’s disease Strains RT-QuIC Alpha-synuclein |
| title | Recursive seed amplification detects distinct α-synuclein strains in cerebrospinal fluid of patients with Parkinson’s disease |
| title_full | Recursive seed amplification detects distinct α-synuclein strains in cerebrospinal fluid of patients with Parkinson’s disease |
| title_fullStr | Recursive seed amplification detects distinct α-synuclein strains in cerebrospinal fluid of patients with Parkinson’s disease |
| title_full_unstemmed | Recursive seed amplification detects distinct α-synuclein strains in cerebrospinal fluid of patients with Parkinson’s disease |
| title_short | Recursive seed amplification detects distinct α-synuclein strains in cerebrospinal fluid of patients with Parkinson’s disease |
| title_sort | recursive seed amplification detects distinct α synuclein strains in cerebrospinal fluid of patients with parkinson s disease |
| topic | Seed amplification assay Parkinson’s disease Strains RT-QuIC Alpha-synuclein |
| url | https://doi.org/10.1186/s40478-024-01923-8 |
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