Abstract
Increasing evidence suggests an important role of alpha-synuclein (α-Syn) in the pathogenesis of Parkinson’s disease (PD). The inter-neuronal spread of α-Syn via exocytosis and endocytosis has been proposed as an explanation for the neuropathological findings of PD in sub-clinical and clinical phases. Therefore, interfering the uptake of α-Syn by neurons may be an important step in slowing or modifying the propagation of the disease. The purposes of our study were to investigate if the uptake of α-Syn fibrils can be specifically interfered with monomeric β-Amyloid1–40 (Aβ40) and to characterise the core acting site of interference. Using a radioisotope-labelled uptake assay, we found an 80 % uptake reduction of α-Syn fibrils in neurons interfered with monomeric Aβ40, but not β-Amyloid1–42 (Aβ42) as compared to controls. This finding was further confirmed by enzyme-linked immunosorbent assay (ELISA) with α-Syn uptake reduced from about 80 % (Aβ42) to about 20 % (Aβ40) relative to controls. To define the region of Aβ40 peptide capable of the interference, we explored shorter peptides with less amino acid residues from both the C-terminus and N-terminus. We found that the interference effect was preserved if amino acid residue was trimmed to position 11 (from N-terminus) and 36 (from C-terminus), but dropped off significantly if residues were trimmed beyond these positions. We therefore deduced that the “core acting site” lies between amino acid residue positions 12–36. These findings suggest α-Syn uptake can be interfered with monomeric Aβ40 and that the core acting site of interference might lie between amino acid residue positions 12–36.
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Acknowledgments
The authors would like to acknowledge the contribution of Dr. Xing Mai Jiang for his useful ideas and comments on the manuscript.
Author's contribution
DKYC, NB, YHX and WPG were involved with the conception, design, and interpretation of data. DKYC and NB performed the experiments. DKYC, NB, YHX and WPG were involved with data analysis. CT collected the clinical material. WPG, TC and FG were involved in production, purification and characterisation of alpha-synuclein proteins and antibodies. DKYC, WPG and GJG provided general overall supervision of the study, and acquired funding. All authors contributed to the drafting and critical revision of the manuscript and have given final approval of the version to be published.
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Chan, D.K.Y., Braidy, N., Xu, Y.H. et al. Interference of α-Synuclein Uptake by Monomeric β-Amyloid1–40 and Potential Core Acting Site of the Interference. Neurotox Res 30, 479–485 (2016). https://doi.org/10.1007/s12640-016-9644-2
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DOI: https://doi.org/10.1007/s12640-016-9644-2