Interference of α-Synuclein Uptake by Monomeric β-Amyloid1-40 and Potential Core Acting Site of the Interference

Increasing evidence suggests an important role of alpha-synuclein (alpha-Syn) in the pathogenesis of Parkinson's disease (PD). The inter-neuronal spread of alpha-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 alpha-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 alpha-Syn fibrils can be specifically interfered with monomeric beta-Amyloid(1-40) (A beta(40)) and to characterise the core acting site of interference. Using a radioisotope-labelled uptake assay, we found an 80 % uptake reduction of alpha-Syn fibrils in neurons interfered with monomeric A beta(40), but not beta-Amyloid(1-42) (A beta(42)) as compared to controls. This finding was further confirmed by enzyme-linked immunosorbent assay (ELISA) with alpha-Syn uptake reduced from about 80 % (A beta(42)) to about 20 % (A beta(40)) relative to controls. To define the region of A beta(40) 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 alpha-Syn uptake can be interfered with monomeric A beta(40) and that the core acting site of interference might lie between amino acid residue positions 12-36.