Format

Send to

Choose Destination
Ann Neurol. 2019 Feb 25. doi: 10.1002/ana.25446. [Epub ahead of print]

Seeding variability of different alpha synuclein strains in synucleinopathies.

Author information

1
Department of Neurology, University Medicine Goettingen and the German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.
2
CIBERNED (Network center for biomedical research of neurodegenerative diseases), Institute Carlos III, Ministry of Health, Spain.
3
Keizo Asami Laboratory (LIKA)Universidade Federal de Pernambuco (UFPE), Recife, Brazil.
4
Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Goettingen, 37075, Germany.
5
Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Waldweg 33. Göttingen, Germany, D-37075.
6
Max Planck Institute for Experimental Medicine Medicine Head of the Electron Microscopy Core Unit Department of Neurogenetics, Göttingen, Germany.
7
Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle, Upon Tyne, NE2 4HH, UK.
8
Departamento de Neuropatología y Banco de Tejidos (BT-CIEN), Fundación CIEN, Instituto de Salud Carlos III Centro Alzheimer Fundación Reina Sofíac/ Valderrebollo n° 5 28031, Madrid.
9
Institute of Applied Physics, National Research Council, via Madonna del Piano, 10 I-50019, Sesto Fiorentino, Italy.

Abstract

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 analyse the seeding activity of Dementia with Lewy bodies (DLB) and Parkinson's disease (PD) brain derived α-synuclein seeds via real-time quaking-induced conversion (RT-QuIC) and to investigate the structure and morphology of the α-synuclein aggregates generated via 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-characterised 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 PK-resistant and fibrillary α-synuclein species in DLB seeded reactions, while 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. This article is protected by copyright. All rights reserved.

KEYWORDS:

RT-QuIC; strain typing; α-synuclein; α-synucleinopathies

PMID:
30805957
DOI:
10.1002/ana.25446

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center