Journal Article

DZNE-2020-06990

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Seeding variability of different alpha synuclein strains in synucleinopathies.

Candelise, N. (First author)DZNE* ; Schmitz, M. (Corresponding author)DZNE* ; Llorens, F. ; Villar-Piqué, A.DZNE* ; Cramm, M.DZNE* ; Thom, T.DZNE* ; Silva-Correia, S.DZNE* ; da Cunha, J. E. G. ; Möbius, W. ; Outeiro, T. F. ; Álvarez, V. G. ; Banchelli, M. ; D'Andrea, C. ; de Angelis, M. ; Zafar, S.DZNE* ; Rabano, A. ; Matteini, P. ; Zerr, I. (Last author)DZNE*

2019
Wiley-Blackwell Hoboken, NJ

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Please use a persistent id in citations: doi:10.1002/ana.25446

Abstract: 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.

Keyword(s): Aged (MeSH) ; Aged, 80 and over (MeSH) ; Brain: metabolism (MeSH) ; Brain: pathology (MeSH) ; Brain Chemistry: physiology (MeSH) ; Female (MeSH) ; Humans (MeSH) ; Male (MeSH) ; Protein Isoforms: analysis (MeSH) ; Protein Isoforms: metabolism (MeSH) ; Spectrum Analysis, Raman: methods (MeSH) ; Synucleinopathies: metabolism (MeSH) ; Synucleinopathies: pathology (MeSH) ; alpha-Synuclein: analysis (MeSH) ; alpha-Synuclein: metabolism (MeSH)

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Contributing Institute(s):

1. Translational Studies and Biomarker (AG Zerr)
2. Ext UMG Zerr (Ext UMG Zerr)

Research Program(s):

1. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)

Appears in the scientific report 2019

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 10 ; JCR ; Nationallizenz ; SCOPUS ; Web of Science Core Collection

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