Structural heterogeneity of α-synuclein fibrils amplified from patient brain extracts

Autor: Markus Zweckstetter, Timo Strohäker, Shu-Hao Liou, Byung Chul Jung, Glenda M. Halliday, Woojin S. Kim, Seung-Jae Lee, Marina Bennati, Claudio O. Fernández, Dietmar Riedel, Stefan Becker
Rok vydání: 2019
Předmět:
0301 basic medicine
Male
Models
Molecular
Synucleinopathies
Protein Conformation
Parkinson's disease
General Physics and Astronomy
Protein aggregation
Biochemistry
law.invention
0302 clinical medicine
Protein structure
law
metabolism [alpha-Synuclein]
lcsh:Science
metabolism [Synucleinopathies]
Aged
80 and over
Multidisciplinary
Chemistry
Brain
Parkinson Disease
Nuclear magnetic resonance spectroscopy
Structural heterogeneity
3. Good health
diagnosis [Multiple System Atrophy]
alpha-Synuclein
Female
ddc:500
diagnosis [Parkinson Disease]
α-synuclein fibrils
Science
metabolism [Parkinson Disease]
diagnosis [Synucleinopathies]
Fibril
Protein Aggregation
Pathological
General Biochemistry
Genetics and Molecular Biology
Article
03 medical and health sciences
Atrophy
metabolism [Protein Aggregation
Pathological]
mental disorders
metabolism [Multiple System Atrophy]
medicine
Humans
metabolism [Tissue Extracts]
Aged
Tissue Extracts
General Chemistry
Multiple System Atrophy
medicine.disease
In vitro
nervous system diseases
030104 developmental biology
chemistry [alpha-Synuclein]
nervous system
metabolism [Brain]
Biophysics
lcsh:Q
Electron microscope
Solution-state NMR
030217 neurology & neurosurgery
Zdroj: Nature Communications
Nature Communications 10(1), 5535 (2019). doi:10.1038/s41467-019-13564-w
Nature Communications, Vol 10, Iss 1, Pp 1-12 (2019)
ISSN: 2041-1723
Popis: Parkinson’s disease (PD) and Multiple System Atrophy (MSA) are clinically distinctive diseases that feature a common neuropathological hallmark of aggregated α-synuclein. Little is known about how differences in α-synuclein aggregate structure affect disease phenotype. Here, we amplified α-synuclein aggregates from PD and MSA brain extracts and analyzed the conformational properties using fluorescent probes, NMR spectroscopy and electron paramagnetic resonance. We also generated and analyzed several in vitro α-synuclein polymorphs. We found that brain-derived α-synuclein fibrils were structurally different to all of the in vitro polymorphs analyzed. Importantly, there was a greater structural heterogeneity among α-synuclein fibrils from the PD brain compared to those from the MSA brain, possibly reflecting on the greater variability of disease phenotypes evident in PD. Our findings have significant ramifications for the use of non-brain-derived α-synuclein fibrils in PD and MSA studies, and raise important questions regarding the one disease-one strain hypothesis in the study of α-synucleinopathies.
Parkinson’s disease (PD) and Multiple System Atrophy (MSA) are characterized by the pathological accumulation of α-synuclein. Here the authors employ fluorescent probes, electron microscopy and NMR spectroscopy to study the properties of α-synuclein aggregates that were amplified from patient brain extracts and observe a greater structural diversity among PD patients compared to MSA patients.
Databáze: OpenAIRE
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