Correlation between Cellular Uptake and Cytotoxicity of Fragmented α-Synuclein Amyloid Fibrils Suggests Intracellular Basis for Toxicity
Journal article, 2020

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.

Parkinson’s disease

cellular uptake

cytotoxicity

amyloid

α-Synuclein

endocytosis

Author

Xiaolu Zhang

Chalmers, Biology and Biological Engineering, Chemical Biology

Emelie Vilhelmsson Wesén

Chalmers, Biology and Biological Engineering, Chemical Biology

Ranjeet Kumar

Chalmers, Biology and Biological Engineering, Chemical Biology

David Bernson

Chalmers, Biology and Biological Engineering, Chemical Biology

Audrey Gallud

Chalmers, Biology and Biological Engineering, Chemical Biology

Alexandra Paul

Chalmers, Biology and Biological Engineering, Chemical Biology

Pernilla Wittung Stafshede

Chalmers, Biology and Biological Engineering, Chemical Biology

Elin Esbjörner Winters

Chalmers, Biology and Biological Engineering, Chemical Biology

ACS Chemical Neuroscience

1948-7193 (ISSN)

Vol. 11 3 233-241

Subject Categories

Biochemistry and Molecular Biology

Neurosciences

DOI

10.1021/acschemneuro.9b00562

PubMed

31894960

More information

Latest update

2/12/2020