TY  - JOUR
AU  - Candelise, Niccolò
AU  - Schmitz, Matthias
AU  - Llorens, Franc
AU  - Villar-Piqué, Anna
AU  - Cramm, Maria
AU  - Thom, Tobias
AU  - Silva-Correia, Susana
AU  - da Cunha, José Eriton Gomes
AU  - Möbius, Wiebke
AU  - Outeiro, Tiago F
AU  - Álvarez, Valentina González
AU  - Banchelli, Martina
AU  - D'Andrea, Cristiano
AU  - de Angelis, Marella
AU  - Zafar, Saima
AU  - Rabano, Alberto
AU  - Matteini, Paolo
AU  - Zerr, Inga
TI  - Seeding variability of different alpha synuclein strains in synucleinopathies.
JO  - Annals of neurology
VL  - 85
IS  - 5
SN  - 0364-5134
CY  - Hoboken, NJ
PB  - Wiley-Blackwell
M1  - DZNE-2020-06990
SP  - 691-703
PY  - 2019
AB  - 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.
KW  - Aged
KW  - Aged, 80 and over
KW  - Brain: metabolism
KW  - Brain: pathology
KW  - Brain Chemistry: physiology
KW  - Female
KW  - Humans
KW  - Male
KW  - Protein Isoforms: analysis
KW  - Protein Isoforms: metabolism
KW  - Spectrum Analysis, Raman: methods
KW  - Synucleinopathies: metabolism
KW  - Synucleinopathies: pathology
KW  - alpha-Synuclein: analysis
KW  - alpha-Synuclein: metabolism
LB  - PUB:(DE-HGF)16
C6  - pmid:30805957
DO  - DOI:10.1002/ana.25446
UR  - https://pub.dzne.de/record/140668
ER  -