Correlation between Cellular Uptake and Cytotoxicity of Fragmented α-Synuclein Amyloid Fibrils Suggests Intracellular Basis for Toxicity
| Autor: | Alexandra Paul, David Bernson, Xiaolu Zhang, Emelie Wesén, Ranjeet Kumar, Elin K. Esbjörner, Audrey Gallud, Pernilla Wittung-Stafshede |
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| Rok vydání: | 2020 |
| Předmět: |
Amyloid
Cellular pathology Physiology Cognitive Neuroscience Endocytic cycle Endocytosis Fibril Biochemistry Protein Aggregates 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Extracellular Humans 030304 developmental biology 0303 health sciences Chemistry Biological Transport Parkinson Disease Cell Biology General Medicine Heparan sulfate nervous system diseases alpha-Synuclein Biophysics Lysosomes 030217 neurology & neurosurgery Intracellular |
| Zdroj: | ACS Chemical Neuroscience. 11:233-241 |
| ISSN: | 1948-7193 |
| DOI: | 10.1021/acschemneuro.9b00562 |
| Popis: | Aggregation and intracellular deposition of the protein α-synuclein is an underlying characteristic of Parkinson's disease. α-Synuclein assemblies also undergo cell-cell spreading, facilitating propagation of their cellular pathology. Understanding how cellular interactions and uptake of extracellular α-synuclein assemblies depend on their physical attributes is therefore important. We prepared fragmented fluorescently labeled α-synuclein amyloid fibrils of different average lengths (∼80 nm to >1 μm) and compared their interactions with SH-SY5Y cells. We report that fibrils of all lengths, but not monomers, bind avidly to the cell surface. Their uptake is inversely dependent on their average size, occurs via a heparan sulfate dependent endocytic route, and appears to have a size cutoff of ∼400 nm. The uptake of α-synuclein fibrils, but not monomers, correlates with their cytotoxicity as measured by reduction in metabolic activity, strongly suggesting an intracellular basis for α-synuclein fibril toxicity, likely involving endolysosomes. |
| Databáze: | OpenAIRE |
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