title: Interference of α-Synuclein Uptake by Monomeric β-Amyloid1-40 and Potential Core Acting Site of the Interference.
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.
authors.affiliation: Faculty of Medicine, University of New South Wales, Sydney, 2052, Australia. d.chan@unsw.edu.au.|Ingham Institute, Liverpool, NSW, 2170, Australia. d.chan@unsw.edu.au.|Department of Aged Care and Rehabilitation, Bankstown-Lidcombe Hospital, Locked Bag 1600, Bankstown, NSW, 2200, Australia. d.chan@unsw.edu.au.
authors.forename: Daniel K Y
authors.initials: DK
authors.lastname: Chan
authors.affiliation: Faculty of Medicine, University of New South Wales, Sydney, 2052, Australia.|Ingham Institute, Liverpool, NSW, 2170, Australia.|Department of Aged Care and Rehabilitation, Bankstown-Lidcombe Hospital, Locked Bag 1600, Bankstown, NSW, 2200, Australia.
authors.forename: Nady
authors.initials: N
authors.lastname: Braidy
authors.affiliation: Faculty of Medicine, University of New South Wales, Sydney, 2052, Australia.|Ingham Institute, Liverpool, NSW, 2170, Australia.|Department of Aged Care and Rehabilitation, Bankstown-Lidcombe Hospital, Locked Bag 1600, Bankstown, NSW, 2200, Australia.
authors.forename: Ying Hua
authors.initials: YH
authors.lastname: Xu
authors.affiliation: Department of Human Physiology and the Centre for Neuroscience, School of Medicine, Flinders University, Bedford Park, SA, 5042, Australia.
authors.forename: Tim
authors.initials: T
authors.lastname: Chataway
authors.affiliation: Department of Human Physiology and the Centre for Neuroscience, School of Medicine, Flinders University, Bedford Park, SA, 5042, Australia.
authors.forename: Feng
authors.initials: F
authors.lastname: Guo
authors.affiliation: Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, 2109, Australia.
authors.forename: Gilles J
authors.initials: GJ
authors.lastname: Guillemin
authors.affiliation: Faculty of Medicine, University of New South Wales, Sydney, 2052, Australia.|Centre for Minimally Invasive Neurosurgery, Randwick, NSW, 2031, Australia.
authors.forename: Charlie
authors.initials: C
authors.lastname: Teo
authors.affiliation: Department of Surgery and Centre for Neuroscience, School of Medicine, Flinders University, Bedford Park, SA, 5042, Australia.
authors.forename: Wei Ping
authors.initials: WP
authors.lastname: Gai
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004705:Endocytosis / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli; D006801:Humans; D006835:Hydrazones / Q000378:metabolism; D007120:Immunochemistry; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D020280:Sertraline / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D006835:Hydrazones; C054369:MAPT protein, human; C511794:N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide; D010446:Peptide Fragments; D011994:Recombinant Proteins; C497604:SNCA protein, human; D051844:alpha-Synuclein; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D020280:Sertraline
keywords: Interference; α-synuclein; α-synuclein uptake; β-amyloid1–40; β-amyloid1–42