Conversion of Wild-type α-Synuclein into Mutant-type Fibrils and Its Propagation in the Presence of A30P Mutant
Fibrillization or conformational change of α-synuclein is central in the pathogenesis of α-synucleinopathies, such as Parkinson disease. We found that the A30P mutant accelerates nucleation-dependent fibrillization of wild type (WT) α-synuclein. Electron microscopy observation and ultracentrifuga...
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Veröffentlicht in: | The Journal of biological chemistry 2009-03, Vol.284 (12), p.7940 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | Fibrillization or conformational change of α-synuclein is central in the pathogenesis of α-synucleinopathies, such as Parkinson
disease. We found that the A30P mutant accelerates nucleation-dependent fibrillization of wild type (WT) α-synuclein. Electron
microscopy observation and ultracentrifugation experiments revealed that shedding of fragments occurs from A30P fibrils and
that these fragments accelerate fibrillization by serving as seeds. Immunochemical analysis using epitope-specific antibodies
and biochemical analyses of protease-resistant cores demonstrated that A30P fibrils have a distinct conformation. Interestingly,
WT fibrils formed with A30P seeds exhibited the same character as A30P fibrils, as did A30P fibrils formed with WT seeds,
indicating that the A30P mutation affects the conformation and fibrillization of both WT and A30P. These effects of A30P mutation
may explain the apparent conflict between the association of A30P with Parkinson disease and the slow fibrillization of A30P
itself and therefore provide new insight into the molecular mechanisms of α-synucleinopathies. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M807482200 |