%0 Journal Article
%A Candelise, Niccolò
%A Schmitz, Matthias
%A Llorens, Franc
%A Villar-Piqué, Anna
%A Cramm, Maria
%A Thom, Tobias
%A Silva-Correia, Susana
%A da Cunha, José Eriton Gomes
%A Möbius, Wiebke
%A Outeiro, Tiago F
%A Álvarez, Valentina González
%A Banchelli, Martina
%A D'Andrea, Cristiano
%A de Angelis, Marella
%A Zafar, Saima
%A Rabano, Alberto
%A Matteini, Paolo
%A Zerr, Inga
%T Seeding variability of different alpha synuclein strains in synucleinopathies.
%J Annals of neurology
%V 85
%N 5
%@ 0364-5134
%C Hoboken, NJ
%I Wiley-Blackwell
%M DZNE-2020-06990
%P 691-703
%D 2019
%X 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.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.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.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.
%K Aged
%K Aged, 80 and over
%K Brain: metabolism
%K Brain: pathology
%K Brain Chemistry: physiology
%K Female
%K Humans
%K Male
%K Protein Isoforms: analysis
%K Protein Isoforms: metabolism
%K Spectrum Analysis, Raman: methods
%K Synucleinopathies: metabolism
%K Synucleinopathies: pathology
%K alpha-Synuclein: analysis
%K alpha-Synuclein: metabolism
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:30805957
%R 10.1002/ana.25446
%U https://pub.dzne.de/record/140668