title: DOPAL derived alpha-synuclein oligomers impair synaptic vesicles physiological function.
abstract: Parkinson's disease is a neurodegenerative disorder characterized by the death of dopaminergic neurons and by accumulation of alpha-synuclein (aS) aggregates in the surviving neurons. The dopamine catabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) is a highly reactive and toxic molecule that leads to aS oligomerization by covalent modifications to lysine residues. Here we show that DOPAL-induced aS oligomer formation in neurons is associated with damage of synaptic vesicles, and with alterations in the synaptic vesicles pools. To investigate the molecular mechanism that leads to synaptic impairment, we first aimed to characterize the biochemical and biophysical properties of the aS-DOPAL oligomers; heterogeneous ensembles of macromolecules able to permeabilise cholesterol-containing lipid membranes. aS-DOPAL oligomers can induce dopamine leak in an in vitro model of synaptic vesicles and in cellular models. The dopamine released, after conversion to DOPAL in the cytoplasm, could trigger a noxious cycle that further fuels the formation of aS-DOPAL oligomers, inducing neurodegeneration.
authors.affiliation: Department of Biology, University of Padova, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Plotegher
authors.affiliation: Department of Biology, University of Padova, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Berti
authors.affiliation: Department of Chemistry, University of Pavia, Italy.|Institute of Biomedical Technologies, National Research Council of Italy, Segrate (Milan), Italy.
authors.forename: E
authors.initials: E
authors.lastname: Ferrari
authors.affiliation: Department of Biology, University of Padova, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Tessari
authors.affiliation: Institute of Biophysics, National Research Council of Italy, Trento, Italy.|Laboratory of Biomolecular Sequence and Structure Analysis for Health, Bruno Kessler Foundation, Trento, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Zanetti
authors.affiliation: Institute of Biophysics, National Research Council of Italy, Trento, Italy.|Laboratory of Biomolecular Sequence and Structure Analysis for Health, Bruno Kessler Foundation, Trento, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Lunelli
authors.affiliation: Department of Biology, University of Padova, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Greggio
authors.affiliation: Department of Biology, University of Padova, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Bisaglia
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genova, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Veronesi
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genova, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Girotto
authors.affiliation: Institute of Biophysics, National Research Council of Italy, Trento, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Dalla Serra
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Perego
authors.affiliation: Department of Chemistry, University of Pavia, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Casella
authors.affiliation: Department of Biology, University of Padova, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Bubacco
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D010539:Permeability; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological; D011485:Protein Binding; D055503:Protein Multimerization / Q000187:drug effects*; D013572:Synaptic Vesicles / Q000187:drug effects* / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D066329:Protein Aggregates; D051844:alpha-Synuclein; D015102:3,4-Dihydroxyphenylacetic Acid; C007430:3,4-dihydroxyphenylacetaldehyde