DOPAL derived alpha-synuclein oligomers impair synaptic vesicles physiological function
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 t...
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| Veröffentlicht in: | Scientific reports 2017-01, Vol.7 (1), p.40699, Article 40699 |
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| creator | 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. |
| description | 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. |
| doi_str_mv | 10.1038/srep40699 |
| format | Article |
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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.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/srep40699</identifier><identifier>PMID: 28084443</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>14/35 ; 631/378/340 ; 631/57/2272 ; 82/6 ; Cholesterol ; Cytoplasm ; Dopamine ; Dopamine receptors ; Humanities and Social Sciences ; Lipid membranes ; Lysine ; Macromolecules ; Movement disorders ; multidisciplinary ; Neurodegeneration ; Neurodegenerative diseases ; Oligomerization ; Parkinson's disease ; Science ; Synaptic vesicles ; Synuclein</subject><ispartof>Scientific reports, 2017-01, Vol.7 (1), p.40699, Article 40699</ispartof><rights>The Author(s) 2017</rights><rights>Copyright Nature Publishing Group Jan 2017</rights><rights>Copyright © 2017, The Author(s) 2017 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c504t-d338ca9064605b64c978e3d6e793a31a75945d89c355b81a40d64609bcc5efe43</citedby><cites>FETCH-LOGICAL-c504t-d338ca9064605b64c978e3d6e793a31a75945d89c355b81a40d64609bcc5efe43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5233976/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5233976/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,41096,42165,51551,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28084443$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Plotegher, N.</creatorcontrib><creatorcontrib>Berti, G.</creatorcontrib><creatorcontrib>Ferrari, E.</creatorcontrib><creatorcontrib>Tessari, I.</creatorcontrib><creatorcontrib>Zanetti, M.</creatorcontrib><creatorcontrib>Lunelli, L.</creatorcontrib><creatorcontrib>Greggio, E.</creatorcontrib><creatorcontrib>Bisaglia, M.</creatorcontrib><creatorcontrib>Veronesi, M.</creatorcontrib><creatorcontrib>Girotto, S.</creatorcontrib><creatorcontrib>Dalla Serra, M.</creatorcontrib><creatorcontrib>Perego, C.</creatorcontrib><creatorcontrib>Casella, L.</creatorcontrib><creatorcontrib>Bubacco, L.</creatorcontrib><title>DOPAL derived alpha-synuclein oligomers impair synaptic vesicles physiological function</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>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.</description><subject>14/35</subject><subject>631/378/340</subject><subject>631/57/2272</subject><subject>82/6</subject><subject>Cholesterol</subject><subject>Cytoplasm</subject><subject>Dopamine</subject><subject>Dopamine receptors</subject><subject>Humanities and Social Sciences</subject><subject>Lipid membranes</subject><subject>Lysine</subject><subject>Macromolecules</subject><subject>Movement disorders</subject><subject>multidisciplinary</subject><subject>Neurodegeneration</subject><subject>Neurodegenerative diseases</subject><subject>Oligomerization</subject><subject>Parkinson's disease</subject><subject>Science</subject><subject>Synaptic vesicles</subject><subject>Synuclein</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>BENPR</sourceid><recordid>eNplkV9LwzAUxYMobsw9-AUk4JNCNW2SNnkRxvwLg_mg-BjSNO0yuqYm7WDf3ozNMfG-3Avnx7mHewG4jNFdjDC79063BKWcn4BhggiNEpwkp0fzAIy9X6JQNOEk5udgkDDECCF4CL4e5--TGSy0M2tdQFm3Cxn5TdOrWpsG2tpUdqWdh2bVSuNgkGTbGQXX2pvAeNguNt7Y2lZGyRqWfaM6Y5sLcFbK2uvxvo_A5_PTx_Q1ms1f3qaTWaQoIl1UYMyU5CglKaJ5ShTPmMZFqjOOJY5lRjmhBeMKU5qzWBJUbFGeK0V1qQkegYedb9vnK10o3XRO1qJ1ZiXdRlhpxF-lMQtR2bWgCcY8S4PB9d7A2e9e-04sbe-akFnEjHPC4gRngbrZUcpZHy5eHjbESGzfIA5vCOzVcaQD-Xv0ANzuAB-kptLuaOU_tx_LipL8</recordid><startdate>20170113</startdate><enddate>20170113</enddate><creator>Plotegher, N.</creator><creator>Berti, G.</creator><creator>Ferrari, E.</creator><creator>Tessari, I.</creator><creator>Zanetti, M.</creator><creator>Lunelli, L.</creator><creator>Greggio, E.</creator><creator>Bisaglia, M.</creator><creator>Veronesi, M.</creator><creator>Girotto, S.</creator><creator>Dalla Serra, M.</creator><creator>Perego, C.</creator><creator>Casella, L.</creator><creator>Bubacco, L.</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>5PM</scope></search><sort><creationdate>20170113</creationdate><title>DOPAL derived alpha-synuclein oligomers impair synaptic vesicles physiological function</title><author>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.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c504t-d338ca9064605b64c978e3d6e793a31a75945d89c355b81a40d64609bcc5efe43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>14/35</topic><topic>631/378/340</topic><topic>631/57/2272</topic><topic>82/6</topic><topic>Cholesterol</topic><topic>Cytoplasm</topic><topic>Dopamine</topic><topic>Dopamine receptors</topic><topic>Humanities and Social Sciences</topic><topic>Lipid membranes</topic><topic>Lysine</topic><topic>Macromolecules</topic><topic>Movement disorders</topic><topic>multidisciplinary</topic><topic>Neurodegeneration</topic><topic>Neurodegenerative diseases</topic><topic>Oligomerization</topic><topic>Parkinson's disease</topic><topic>Science</topic><topic>Synaptic vesicles</topic><topic>Synuclein</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Plotegher, N.</creatorcontrib><creatorcontrib>Berti, G.</creatorcontrib><creatorcontrib>Ferrari, E.</creatorcontrib><creatorcontrib>Tessari, I.</creatorcontrib><creatorcontrib>Zanetti, M.</creatorcontrib><creatorcontrib>Lunelli, L.</creatorcontrib><creatorcontrib>Greggio, E.</creatorcontrib><creatorcontrib>Bisaglia, M.</creatorcontrib><creatorcontrib>Veronesi, M.</creatorcontrib><creatorcontrib>Girotto, S.</creatorcontrib><creatorcontrib>Dalla Serra, M.</creatorcontrib><creatorcontrib>Perego, C.</creatorcontrib><creatorcontrib>Casella, L.</creatorcontrib><creatorcontrib>Bubacco, L.</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Plotegher, N.</au><au>Berti, G.</au><au>Ferrari, E.</au><au>Tessari, I.</au><au>Zanetti, M.</au><au>Lunelli, L.</au><au>Greggio, E.</au><au>Bisaglia, M.</au><au>Veronesi, M.</au><au>Girotto, S.</au><au>Dalla Serra, M.</au><au>Perego, C.</au><au>Casella, L.</au><au>Bubacco, L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>DOPAL derived alpha-synuclein oligomers impair synaptic vesicles physiological function</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2017-01-13</date><risdate>2017</risdate><volume>7</volume><issue>1</issue><spage>40699</spage><pages>40699-</pages><artnum>40699</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>28084443</pmid><doi>10.1038/srep40699</doi><oa>free_for_read</oa></addata></record> |
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| subjects | 14/35 631/378/340 631/57/2272 82/6 Cholesterol Cytoplasm Dopamine Dopamine receptors Humanities and Social Sciences Lipid membranes Lysine Macromolecules Movement disorders multidisciplinary Neurodegeneration Neurodegenerative diseases Oligomerization Parkinson's disease Science Synaptic vesicles Synuclein |
| title | DOPAL derived alpha-synuclein oligomers impair synaptic vesicles physiological function |
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