Seeding variability of different alpha synuclein strains in synucleinopathies

Candelise, Niccolo; Schmitz, Matthias; Llorens, Franc; Villar-Piqué, Anna; Cramm, Maria; Thom, Tobias; da Silva Correia, Susana Margarida; Gomes da Cunha, José Eriton; Möbius, Wiebke; Outeiro, Tiago F.; González Álvarez, Valentina; Banchelli, Martina; D'Andrea, Cristiano; de Angelis, Marella; Zafar, Saima; Rabano, Alberto; Matteini, Paolo; Zerr, Inga

doi:10.1002/ana.25446

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Seeding variability of different alpha synuclein strains in synucleinopathies

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Möbius, Wiebke
Electron microscopy, Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

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Outeiro, Tiago F.
Experimental Neurodegeneration, Max Planck Institute of Experimental Medicine, Max Planck Society;

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引用

Candelise, N., Schmitz, M., Llorens, F., Villar-Piqué, A., Cramm, M., Thom, T., da Silva Correia, S. M., Gomes da Cunha, J. E., Möbius, W., Outeiro, T. F., González Álvarez, V., Banchelli, M., D'Andrea, C., de Angelis, M., Zafar, S., Rabano, A., Matteini, P., & Zerr, I. (2019). Seeding variability of different alpha synuclein strains in synucleinopathies. Annals of Neurology, 85(5), 691-703. doi:10.1002/ana.25446.

引用: https://hdl.handle.net/21.11116/0000-0003-1828-6

要旨

Objectives:
Currently, the exact reasons why different α-synucleinopathies exhibit variable pathologies and phenotypes are still unknown. A potential explanation may be the existence of distinctive α-synuclein conformers or strains. Here, we intend to analyze the seeding activity of dementia with Lewy bodies (DLB) and Parkinson's disease (PD) brain-derived α-synuclein seeds by real-time quaking-induced conversion (RT-QuIC) and to investigate the structure and morphology of the α-synuclein aggregates generated by RT-QuIC.

Methods:
A misfolded α-synuclein–enriched brain fraction from frontal cortex and substantia nigra pars compacta tissue, isolated by several filtration and centrifugation steps, was subjected to α-synuclein/RT-QuIC analysis. Our study included neuropathologically well-characterized cases with DLB, PD, and controls (Ctrl). Biochemical and morphological analyses of RT-QuIC products were conducted by western blot, dot blot analysis, Raman spectroscopy, atomic force microscopy, and transmission electron microscopy.

Results:
Independently from the brain region, we observed different seeding kinetics of α-synuclein in the RT-QuIC in patients with DLB compared to PD and Ctrl. Biochemical characterization of the RT-QuIC product indicated the generation of a proteinase K–resistant and fibrillary α-synuclein species in DLB-seeded reactions, whereas PD and control seeds failed in the conversion of wild-type α-synuclein substrate.

Interpretation:
Structural variances of α-synuclein seeding kinetics and products in DLB and PD indicated, for the first time, the existence of different α-synuclein strains in these groups. Therefore, our study contributes to a better understanding of the clinical heterogeneity among α-synucleinopathies, offers an opportunity for a specific diagnosis, and opens new avenues for the future development of strain-specific therapies. Ann Neurol 2019;85:691–703