| 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 | Plotegher N, Berti G, Ferrari E, Tessari I, Zanetti M, Lunelli L, Greggio E, Bisaglia M, Veronesi M, Girotto S, Dalla Serra M, Perego C, Casella L, Bubacco L |
| Text | 374176 2017 10.1038/srep40699 Scopus 2 s2.0 85009484076 ISI Web of Science WOS 000391925800001 PubMed 28084443 Toxic dopamine metabolite; Parkinsons disease; Recycling pool; Membrane; Aldehyde; 3 4 Dihydroxyphenylacetaldehyde; Cells; Pathogenesis; Homeostasis DOPAL derived alpha synuclein oligomers impair synaptic vesicles physiological function Plotegher N, Berti G, Ferrari E, Tessari I, Zanetti M, Lunelli L, Greggio E, Bisaglia M, Veronesi M, Girotto S, Dalla Serra M, Perego C, Casella L, Bubacco L Department of Biology, University of Padova, Italy; Department of Chemistry, University of Pavia, Italy; Institute of Biomedical Technologies, National Research Council of Italy, Segrate Milan , Italy; Institute of Biophysics, National Research Council of Italy, Trento, Italy; Laboratory of Biomolecular Sequence and Structure Analysis for Health, Bruno Kessler Foundation, Trento, Italy; Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genova, Italy; Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy; Department of Developmental and Cell Biology, University College London, United Kingdom 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. 7 Published version http //www.scopus.com/inward/record.url eid=2 s2.0 85009484076 partnerID=q2rCbXpz DOPAL derived alpha synuclein oligomers impair synaptic vesicles physiological function Scientific_Reports_7_40699.pdf Articolo in rivista Nature Publishing Group 2045 2322 Scientific reports Nature Publishing Group Scientific reports Nature Publishing Group Scientific reports Nature Publishing Group lorenzolunelli LUNELLI LORENZO emanuele.ferrari FERRARI EMANUELE mauro.dallaserra DALLA SERRA MAURO MD.P01.028.001 Membrane biologiche, complessi macromolecolari e imaging biomolecolare |
