The small molecule -2 inhibits the aggregation and seeded polymerisation of C-terminally truncated α-Synuclein
Protein aggregation, particularly the formation of amyloid fibrils, is associated with numerous human disorders, including Parkinson's disease. This neurodegenerative condition is characterised by the accumulation of α-Synuclein amyloid fibrils within intraneuronal deposits known as Lewy bodies...
| Autores: | , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Universitat Autònoma de Barcelona |
| Repositorio: | Dipòsit Digital de Documents de la UAB |
| Idioma: | inglés |
| OAI Identifier: | oai:ddd.uab.cat:307580 |
| Acceso en línea: | https://ddd.uab.cat/record/307580 https://dx.doi.org/urn:doi:10.1111/febs.17310 |
| Access Level: | acceso abierto |
| Palabra clave: | Inhibition Oligomer Protein aggregation Truncation α-Synuclein |
| Sumario: | Protein aggregation, particularly the formation of amyloid fibrils, is associated with numerous human disorders, including Parkinson's disease. This neurodegenerative condition is characterised by the accumulation of α-Synuclein amyloid fibrils within intraneuronal deposits known as Lewy bodies or neurites. C-terminally truncated forms of α-Synuclein are frequently observed in these inclusions in the brains of patients, and their increased aggregation propensity suggests a role in the disease's pathogenesis. This study demonstrates that the small molecule ZPD-2 acts as a potent inhibitor of both the spontaneous and seeded amyloid polimerisation of C-terminally truncated α-Synuclein by interfering with early aggregation intermediates. This dual activity positions this molecule as a promising candidate for therapeutic development in treating synucleinopathies. The aggregation of α-Synuclein plays a key role in Parkinson's disease. Remarkably, the C-terminal region of this protein contributes to inhibit amyloid formation and its truncation enhances this process. In this work, we demonstrated that the addition of small molecules, ZPD-2 or SynuClean-D, inhibits the aggregation of C-terminally truncated α-Synuclein. Overall, the data suggested different inhibitory mechanisms with ZPD-2 outperforming SC-D by acting at the initial stages of aggregation. |
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