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 |
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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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