Temperature-dependent structural changes of Parkinson's alpha-synuclein reveal the role of pre-existing oligomers in alpha-synuclein fibrillization
Amyloid fibrils of α-synuclein are the main constituent of Lewy bodies deposited in substantial nigra of Parkinson's disease brains. α-Synuclein is an intrinsically disordered protein lacking compact secondary and tertiary structures. To enhance the understanding of its structure and function r...
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| description | Amyloid fibrils of α-synuclein are the main constituent of Lewy bodies deposited in substantial nigra of Parkinson's disease brains. α-Synuclein is an intrinsically disordered protein lacking compact secondary and tertiary structures. To enhance the understanding of its structure and function relationship, we utilized temperature treatment to study α-synuclein conformational changes and the subsequent effects. We found that after 1 hr of high temperature pretreatment, >80°C, α-synuclein fibrillization was significantly inhibited. However, the temperature melting coupled with circular dichroism spectra showed that α-synuclein was fully reversible and the NMR studies showed no observable structural changes of α-synuclein after 95°C treatment. By using cross-linking and analytical ultracentrifugation, rare amount of pre-existing α-synuclein oligomers were found to decrease after the high temperature treatment. In addition, a small portion of C-terminal truncation of α-synuclein also occurred. The reduction of pre-existing oligomers of α-synuclein may contribute to less seeding effect that retards the kinetics of amyloid fibrillization. Overall, our results showed that the pre-existing oligomeric species is a key factor contributing to α-synuclein fibrillization. Our results facilitate the understanding of α-synuclein fibrillization. |
| doi_str_mv | 10.1371/journal.pone.0053487 |
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To enhance the understanding of its structure and function relationship, we utilized temperature treatment to study α-synuclein conformational changes and the subsequent effects. We found that after 1 hr of high temperature pretreatment, >80°C, α-synuclein fibrillization was significantly inhibited. However, the temperature melting coupled with circular dichroism spectra showed that α-synuclein was fully reversible and the NMR studies showed no observable structural changes of α-synuclein after 95°C treatment. By using cross-linking and analytical ultracentrifugation, rare amount of pre-existing α-synuclein oligomers were found to decrease after the high temperature treatment. In addition, a small portion of C-terminal truncation of α-synuclein also occurred. The reduction of pre-existing oligomers of α-synuclein may contribute to less seeding effect that retards the kinetics of amyloid fibrillization. Overall, our results showed that the pre-existing oligomeric species is a key factor contributing to α-synuclein fibrillization. Our results facilitate the understanding of α-synuclein fibrillization.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0053487</identifier><identifier>PMID: 23349712</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>alpha-Synuclein - chemistry ; alpha-Synuclein - genetics ; Alzheimer's disease ; Amino acids ; Amyloid ; Biochemistry ; Biology ; Biophysics ; Circular dichroism ; Crosslinking ; Dichroism ; Dopamine ; E coli ; Fibrillogenesis ; Fibrils ; Fourier transforms ; Genomics ; High temperature ; Humans ; Kinetics ; Lewy bodies ; Medicine ; Movement disorders ; Mutation ; Neurodegenerative diseases ; NMR ; Nuclear magnetic resonance ; Oligomers ; Parkinson Disease - metabolism ; Parkinson's disease ; Physics ; Physiology ; Protein Denaturation ; Protein expression ; Protein Multimerization ; Protein seeding ; Protein Structure, Secondary ; Proteins ; Sequence Deletion ; Structure-function relationships ; Synuclein ; Temperature ; Temperature effects ; Ultracentrifugation</subject><ispartof>PloS one, 2013-01, Vol.8 (1), p.e53487</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Ariesandi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Ariesandi et al 2013 Ariesandi et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-712ff5f2ff1ab926e6e8afbe3fe918822484c5562ca6a1a83d6fbf95808021033</citedby><cites>FETCH-LOGICAL-c758t-712ff5f2ff1ab926e6e8afbe3fe918822484c5562ca6a1a83d6fbf95808021033</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/PMC3551866/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3551866/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23349712$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Baskakov, Ilia V.</contributor><creatorcontrib>Ariesandi, Winny</creatorcontrib><creatorcontrib>Chang, Chi-Fon</creatorcontrib><creatorcontrib>Chen, Tseng-Erh</creatorcontrib><creatorcontrib>Chen, Yun-Ru</creatorcontrib><title>Temperature-dependent structural changes of Parkinson's alpha-synuclein reveal the role of pre-existing oligomers in alpha-synuclein fibrillization</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Amyloid fibrils of α-synuclein are the main constituent of Lewy bodies deposited in substantial nigra of Parkinson's disease brains. α-Synuclein is an intrinsically disordered protein lacking compact secondary and tertiary structures. To enhance the understanding of its structure and function relationship, we utilized temperature treatment to study α-synuclein conformational changes and the subsequent effects. We found that after 1 hr of high temperature pretreatment, >80°C, α-synuclein fibrillization was significantly inhibited. However, the temperature melting coupled with circular dichroism spectra showed that α-synuclein was fully reversible and the NMR studies showed no observable structural changes of α-synuclein after 95°C treatment. By using cross-linking and analytical ultracentrifugation, rare amount of pre-existing α-synuclein oligomers were found to decrease after the high temperature treatment. In addition, a small portion of C-terminal truncation of α-synuclein also occurred. The reduction of pre-existing oligomers of α-synuclein may contribute to less seeding effect that retards the kinetics of amyloid fibrillization. Overall, our results showed that the pre-existing oligomeric species is a key factor contributing to α-synuclein fibrillization. Our results facilitate the understanding of α-synuclein fibrillization.</description><subject>alpha-Synuclein - chemistry</subject><subject>alpha-Synuclein - genetics</subject><subject>Alzheimer's disease</subject><subject>Amino acids</subject><subject>Amyloid</subject><subject>Biochemistry</subject><subject>Biology</subject><subject>Biophysics</subject><subject>Circular dichroism</subject><subject>Crosslinking</subject><subject>Dichroism</subject><subject>Dopamine</subject><subject>E coli</subject><subject>Fibrillogenesis</subject><subject>Fibrils</subject><subject>Fourier transforms</subject><subject>Genomics</subject><subject>High temperature</subject><subject>Humans</subject><subject>Kinetics</subject><subject>Lewy bodies</subject><subject>Medicine</subject><subject>Movement disorders</subject><subject>Mutation</subject><subject>Neurodegenerative diseases</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Oligomers</subject><subject>Parkinson Disease - metabolism</subject><subject>Parkinson's disease</subject><subject>Physics</subject><subject>Physiology</subject><subject>Protein Denaturation</subject><subject>Protein expression</subject><subject>Protein Multimerization</subject><subject>Protein seeding</subject><subject>Protein Structure, Secondary</subject><subject>Proteins</subject><subject>Sequence Deletion</subject><subject>Structure-function relationships</subject><subject>Synuclein</subject><subject>Temperature</subject><subject>Temperature effects</subject><subject>Ultracentrifugation</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk2Fr1TAUhosobk7_gWhBUPah16RJ2_SLMIa6C4OJTr-GtD1pc22TLknH5t_wD5vr7catKEihDSfPeXvy5pwoeo7RCpMCv92YyWrRr0ajYYVQRigrHkSHuCRpkqeIPNxbH0RPnNtsIZbnj6ODlBBaFjg9jH5ewjCCFX6ykDQwgm5A-9h5O9UhJvq47oRuwcVGxp-E_a60M_qNi0U_diJxt3qqe1A6tnANgfYdxNb0sMXHIAk3ynml29j0qjUDWBcH-M9kqSqr-l79EF4Z_TR6JEXv4Nn8PYq-fnh_eXqWnF98XJ-enCd1kTGfhPqlzGR4YVGVaQ45MCErIBJKzFiaUkbrLMvTWuQCC0aaXFayzBhiKMWIkKPo5U537I3js5-OY5IWrCwpzgKx3hGNERs-WjUIe8uNUPx3wNiWC-tVOAQHCQIxwqpwDVSWjMkK54hQzIqsQZQFrXfz36ZqgKYONgd7F6LLHa063pprTrIMh2sLAq9mAWuuJnD-HyXPVCtCVUpLE8TqQbman9CC4bxAlAZq9RcqPA0Mqg4dJVWILxKOFwmB8XDjWzE5x9dfPv8_e_Ftyb7eY7vQQr5zpp-2feCWIN2BtTXOWZD3zmHEtwNx5wbfDgSfByKkvdh3_T7pbgLIL7tKCYQ</recordid><startdate>20130122</startdate><enddate>20130122</enddate><creator>Ariesandi, Winny</creator><creator>Chang, Chi-Fon</creator><creator>Chen, Tseng-Erh</creator><creator>Chen, Yun-Ru</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20130122</creationdate><title>Temperature-dependent structural changes of Parkinson's alpha-synuclein reveal the role of pre-existing oligomers in alpha-synuclein fibrillization</title><author>Ariesandi, Winny ; Chang, Chi-Fon ; Chen, Tseng-Erh ; Chen, Yun-Ru</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c758t-712ff5f2ff1ab926e6e8afbe3fe918822484c5562ca6a1a83d6fbf95808021033</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>alpha-Synuclein - chemistry</topic><topic>alpha-Synuclein - genetics</topic><topic>Alzheimer's disease</topic><topic>Amino acids</topic><topic>Amyloid</topic><topic>Biochemistry</topic><topic>Biology</topic><topic>Biophysics</topic><topic>Circular dichroism</topic><topic>Crosslinking</topic><topic>Dichroism</topic><topic>Dopamine</topic><topic>E coli</topic><topic>Fibrillogenesis</topic><topic>Fibrils</topic><topic>Fourier transforms</topic><topic>Genomics</topic><topic>High temperature</topic><topic>Humans</topic><topic>Kinetics</topic><topic>Lewy bodies</topic><topic>Medicine</topic><topic>Movement disorders</topic><topic>Mutation</topic><topic>Neurodegenerative diseases</topic><topic>NMR</topic><topic>Nuclear magnetic resonance</topic><topic>Oligomers</topic><topic>Parkinson Disease - metabolism</topic><topic>Parkinson's disease</topic><topic>Physics</topic><topic>Physiology</topic><topic>Protein Denaturation</topic><topic>Protein expression</topic><topic>Protein Multimerization</topic><topic>Protein seeding</topic><topic>Protein Structure, Secondary</topic><topic>Proteins</topic><topic>Sequence Deletion</topic><topic>Structure-function relationships</topic><topic>Synuclein</topic><topic>Temperature</topic><topic>Temperature effects</topic><topic>Ultracentrifugation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ariesandi, Winny</creatorcontrib><creatorcontrib>Chang, Chi-Fon</creatorcontrib><creatorcontrib>Chen, Tseng-Erh</creatorcontrib><creatorcontrib>Chen, Yun-Ru</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology 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>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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To enhance the understanding of its structure and function relationship, we utilized temperature treatment to study α-synuclein conformational changes and the subsequent effects. We found that after 1 hr of high temperature pretreatment, >80°C, α-synuclein fibrillization was significantly inhibited. However, the temperature melting coupled with circular dichroism spectra showed that α-synuclein was fully reversible and the NMR studies showed no observable structural changes of α-synuclein after 95°C treatment. By using cross-linking and analytical ultracentrifugation, rare amount of pre-existing α-synuclein oligomers were found to decrease after the high temperature treatment. In addition, a small portion of C-terminal truncation of α-synuclein also occurred. The reduction of pre-existing oligomers of α-synuclein may contribute to less seeding effect that retards the kinetics of amyloid fibrillization. Overall, our results showed that the pre-existing oligomeric species is a key factor contributing to α-synuclein fibrillization. Our results facilitate the understanding of α-synuclein fibrillization.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23349712</pmid><doi>10.1371/journal.pone.0053487</doi><tpages>e53487</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | alpha-Synuclein - chemistry alpha-Synuclein - genetics Alzheimer's disease Amino acids Amyloid Biochemistry Biology Biophysics Circular dichroism Crosslinking Dichroism Dopamine E coli Fibrillogenesis Fibrils Fourier transforms Genomics High temperature Humans Kinetics Lewy bodies Medicine Movement disorders Mutation Neurodegenerative diseases NMR Nuclear magnetic resonance Oligomers Parkinson Disease - metabolism Parkinson's disease Physics Physiology Protein Denaturation Protein expression Protein Multimerization Protein seeding Protein Structure, Secondary Proteins Sequence Deletion Structure-function relationships Synuclein Temperature Temperature effects Ultracentrifugation |
| title | Temperature-dependent structural changes of Parkinson's alpha-synuclein reveal the role of pre-existing oligomers in alpha-synuclein fibrillization |
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