Blocking the FKBP12 induced dendrimeric burst in aberrant aggregation of α-synuclein by using the ElteN378 synthetic inhibitor
α-Synuclein (α-syn), a disordered cytoplasmatic protein, plays a fundamental role in the pathogenesis of Parkinson's disease (PD). Here, we have shown, using photophysical measurements, that addition of FKBP12 to α-syn solutions, dramatically accelerates protein aggregation, leading to an explo...
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| Main Authors: | , , , |
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| Format: | Book |
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Taylor & Francis Group,
2019-01-01T00:00:00Z.
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| Online Access: | Connect to this object online. |
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| Summary: | α-Synuclein (α-syn), a disordered cytoplasmatic protein, plays a fundamental role in the pathogenesis of Parkinson's disease (PD). Here, we have shown, using photophysical measurements, that addition of FKBP12 to α-syn solutions, dramatically accelerates protein aggregation, leading to an explosion of dendritic structures revealed by fluorescence and phase-contrast microscopy. We have further demonstrated that this aberrant α-syn aggregation can be blocked using a recently discovered non-immunosuppressive synthetic inhibitor of FKBP12, ElteN378. The role of FKBP12 and of ElteN378 in the α-syn aggregation mechanism has been elucidated using molecular dynamics simulations based on an effective coarse-grained model. The reported data not only reveal a new potent synthetic drug as a candidate for early stage treatment of α-syn dependent neurodegenerations but also pave the way to a deeper understanding of the mechanism of action of FKBP12 on α-syn oligomeric aggregation, a topic which is still controversial. |
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| Item Description: | 1475-6366 1475-6374 10.1080/14756366.2019.1667342 |