Cytosolic proteins regulate alpha-synuclein dissociation from presynaptic membranes.
Identifieur interne : 000673 ( Ncbi/Merge ); précédent : 000672; suivant : 000674Cytosolic proteins regulate alpha-synuclein dissociation from presynaptic membranes.
Auteurs : Sabine Wislet-Gendebien [Canada] ; Cheryl D'Souza ; Toshitaka Kawarai ; Peter St George-Hyslop ; David Westaway ; Paul Fraser ; Anurag TandonSource :
- The Journal of biological chemistry [ 0021-9258 ] ; 2006.
English descriptors
- KwdEn :
- Animals, Brain Chemistry, Cytosol (chemistry), Gene Expression Regulation, Kinetics, Mice, Mice, Transgenic, Parkinson Disease (genetics), Parkinson Disease (metabolism), Proteins (chemistry), Proteins (genetics), Proteins (metabolism), Synaptic Membranes (metabolism), Synaptosomes (metabolism), Temperature, Up-Regulation, alpha-Synuclein (analysis), alpha-Synuclein (genetics), alpha-Synuclein (metabolism).
- MESH :
- chemical , analysis : alpha-Synuclein.
- chemical , chemistry : Proteins.
- chemistry : Cytosol.
- genetics : Parkinson Disease, Proteins, alpha-Synuclein.
- metabolism : Parkinson Disease, Proteins, Synaptic Membranes, Synaptosomes, alpha-Synuclein.
- Animals, Brain Chemistry, Gene Expression Regulation, Kinetics, Mice, Mice, Transgenic, Temperature, Up-Regulation.
Abstract
Intracellular accumulation of insoluble alpha-synuclein in Lewy bodies is a key neuropathological trait of Parkinson disease (PD). Neither the normal function of alpha-synuclein nor the biochemical mechanisms that cause its deposition are understood, although both are likely influenced by the interaction of alpha-synuclein with vesicular membranes, either for a physiological role in vesicular trafficking or as a pathological seeding mechanism that exacerbates the propensity of alpha-synuclein to self-assemble into fibrils. In addition to the alpha-helical form that is peripherally-attached to vesicles, a substantial portion of alpha-synuclein is freely diffusible in the cytoplasm. The mechanisms controlling alpha-synuclein exchange between these compartments are unknown and the possibility that chronic dysregulation of membrane-bound and soluble alpha-synuclein pools may contribute to Lewy body pathology led us to search for cellular factors that can regulate alpha-synuclein membrane interactions. Here we reveal that dissociation of membrane-bound alpha-synuclein is dependent on brain-specific cytosolic proteins and insensitive to calcium or metabolic energy. Two PD-linked mutations (A30P and A53T) significantly increase the cytosol-dependent alpha-synuclein off-rate but have no effect on cytosol-independent dissociation. These results reveal a novel mechanism by which cytosolic brain proteins modulate alpha-synuclein interactions with intracellular membranes. Importantly, our finding that alpha-synuclein dissociation is up-regulated by both familial PD mutations implicates cytosolic cofactors in disease pathogenesis and as molecular targets to influence alpha-synuclein aggregation.
DOI: 10.1074/jbc.M605965200
PubMed: 16926154
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Park Crescent West, Toronto, Ontario M5S 3H2, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen's Park Crescent West, Toronto, Ontario M5S 3H2</wicri:regionArea><orgName type="university">Université de Toronto</orgName><placeName><settlement type="city">Toronto</settlement><region type="state">Ontario</region></placeName></affiliation></author><author><name sortKey="D Souza, Cheryl" sort="D Souza, Cheryl" uniqKey="D Souza C" first="Cheryl" last="D'Souza">Cheryl D'Souza</name></author><author><name sortKey="Kawarai, Toshitaka" sort="Kawarai, Toshitaka" uniqKey="Kawarai T" first="Toshitaka" last="Kawarai">Toshitaka Kawarai</name></author><author><name sortKey="St George Hyslop, Peter" sort="St George Hyslop, Peter" uniqKey="St George Hyslop P" first="Peter" last="St George-Hyslop">Peter St George-Hyslop</name></author><author><name sortKey="Westaway, David" sort="Westaway, David" uniqKey="Westaway D" first="David" last="Westaway">David Westaway</name></author><author><name sortKey="Fraser, Paul" sort="Fraser, Paul" uniqKey="Fraser P" first="Paul" last="Fraser">Paul Fraser</name></author><author><name sortKey="Tandon, Anurag" sort="Tandon, Anurag" uniqKey="Tandon A" first="Anurag" last="Tandon">Anurag Tandon</name></author></analytic><series><title level="j">The Journal of biological chemistry</title><idno type="ISSN">0021-9258</idno><imprint><date when="2006" type="published">2006</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Brain Chemistry</term><term>Cytosol (chemistry)</term><term>Gene Expression Regulation</term><term>Kinetics</term><term>Mice</term><term>Mice, Transgenic</term><term>Parkinson Disease (genetics)</term><term>Parkinson Disease (metabolism)</term><term>Proteins (chemistry)</term><term>Proteins (genetics)</term><term>Proteins (metabolism)</term><term>Synaptic Membranes (metabolism)</term><term>Synaptosomes (metabolism)</term><term>Temperature</term><term>Up-Regulation</term><term>alpha-Synuclein (analysis)</term><term>alpha-Synuclein (genetics)</term><term>alpha-Synuclein (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analysis" xml:lang="en"><term>alpha-Synuclein</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Proteins</term></keywords><keywords scheme="MESH" qualifier="chemistry" xml:lang="en"><term>Cytosol</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Parkinson Disease</term><term>Proteins</term><term>alpha-Synuclein</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Parkinson Disease</term><term>Proteins</term><term>Synaptic Membranes</term><term>Synaptosomes</term><term>alpha-Synuclein</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Brain Chemistry</term><term>Gene Expression Regulation</term><term>Kinetics</term><term>Mice</term><term>Mice, Transgenic</term><term>Temperature</term><term>Up-Regulation</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Intracellular accumulation of insoluble alpha-synuclein in Lewy bodies is a key neuropathological trait of Parkinson disease (PD). Neither the normal function of alpha-synuclein nor the biochemical mechanisms that cause its deposition are understood, although both are likely influenced by the interaction of alpha-synuclein with vesicular membranes, either for a physiological role in vesicular trafficking or as a pathological seeding mechanism that exacerbates the propensity of alpha-synuclein to self-assemble into fibrils. In addition to the alpha-helical form that is peripherally-attached to vesicles, a substantial portion of alpha-synuclein is freely diffusible in the cytoplasm. The mechanisms controlling alpha-synuclein exchange between these compartments are unknown and the possibility that chronic dysregulation of membrane-bound and soluble alpha-synuclein pools may contribute to Lewy body pathology led us to search for cellular factors that can regulate alpha-synuclein membrane interactions. Here we reveal that dissociation of membrane-bound alpha-synuclein is dependent on brain-specific cytosolic proteins and insensitive to calcium or metabolic energy. Two PD-linked mutations (A30P and A53T) significantly increase the cytosol-dependent alpha-synuclein off-rate but have no effect on cytosol-independent dissociation. These results reveal a novel mechanism by which cytosolic brain proteins modulate alpha-synuclein interactions with intracellular membranes. Importantly, our finding that alpha-synuclein dissociation is up-regulated by both familial PD mutations implicates cytosolic cofactors in disease pathogenesis and as molecular targets to influence alpha-synuclein aggregation.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">16926154</PMID><DateCreated><Year>2006</Year><Month>10</Month><Day>23</Day></DateCreated><DateCompleted><Year>2006</Year><Month>12</Month><Day>07</Day></DateCompleted><DateRevised><Year>2006</Year><Month>10</Month><Day>23</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Print">0021-9258</ISSN><JournalIssue CitedMedium="Print"><Volume>281</Volume><Issue>43</Issue><PubDate><Year>2006</Year><Month>Oct</Month><Day>27</Day></PubDate></JournalIssue><Title>The Journal of biological chemistry</Title><ISOAbbreviation>J. Biol. Chem.</ISOAbbreviation></Journal><ArticleTitle>Cytosolic proteins regulate alpha-synuclein dissociation from presynaptic membranes.</ArticleTitle><Pagination><MedlinePgn>32148-55</MedlinePgn></Pagination><Abstract><AbstractText>Intracellular accumulation of insoluble alpha-synuclein in Lewy bodies is a key neuropathological trait of Parkinson disease (PD). Neither the normal function of alpha-synuclein nor the biochemical mechanisms that cause its deposition are understood, although both are likely influenced by the interaction of alpha-synuclein with vesicular membranes, either for a physiological role in vesicular trafficking or as a pathological seeding mechanism that exacerbates the propensity of alpha-synuclein to self-assemble into fibrils. In addition to the alpha-helical form that is peripherally-attached to vesicles, a substantial portion of alpha-synuclein is freely diffusible in the cytoplasm. The mechanisms controlling alpha-synuclein exchange between these compartments are unknown and the possibility that chronic dysregulation of membrane-bound and soluble alpha-synuclein pools may contribute to Lewy body pathology led us to search for cellular factors that can regulate alpha-synuclein membrane interactions. Here we reveal that dissociation of membrane-bound alpha-synuclein is dependent on brain-specific cytosolic proteins and insensitive to calcium or metabolic energy. Two PD-linked mutations (A30P and A53T) significantly increase the cytosol-dependent alpha-synuclein off-rate but have no effect on cytosol-independent dissociation. These results reveal a novel mechanism by which cytosolic brain proteins modulate alpha-synuclein interactions with intracellular membranes. Importantly, our finding that alpha-synuclein dissociation is up-regulated by both familial PD mutations implicates cytosolic cofactors in disease pathogenesis and as molecular targets to influence alpha-synuclein aggregation.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Wislet-Gendebien</LastName><ForeName>Sabine</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen's Park Crescent West, Toronto, Ontario M5S 3H2, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>D'Souza</LastName><ForeName>Cheryl</ForeName><Initials>C</Initials></Author><Author ValidYN="Y"><LastName>Kawarai</LastName><ForeName>Toshitaka</ForeName><Initials>T</Initials></Author><Author ValidYN="Y"><LastName>St George-Hyslop</LastName><ForeName>Peter</ForeName><Initials>P</Initials></Author><Author ValidYN="Y"><LastName>Westaway</LastName><ForeName>David</ForeName><Initials>D</Initials></Author><Author ValidYN="Y"><LastName>Fraser</LastName><ForeName>Paul</ForeName><Initials>P</Initials></Author><Author ValidYN="Y"><LastName>Tandon</LastName><ForeName>Anurag</ForeName><Initials>A</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D003160">Comparative Study</PublicationType><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2006</Year><Month>08</Month><Day>22</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>J Biol Chem</MedlineTA><NlmUniqueID>2985121R</NlmUniqueID><ISSNLinking>0021-9258</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance 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IdType="pubmed">16926154</ArticleId><ArticleId IdType="pii">M605965200</ArticleId><ArticleId IdType="doi">10.1074/jbc.M605965200</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Canada</li></country><region><li>Ontario</li></region><settlement><li>Toronto</li></settlement><orgName><li>Université de Toronto</li></orgName></list><tree><noCountry><name sortKey="D Souza, Cheryl" sort="D Souza, Cheryl" uniqKey="D Souza C" first="Cheryl" last="D'Souza">Cheryl D'Souza</name><name sortKey="Fraser, Paul" sort="Fraser, Paul" uniqKey="Fraser P" first="Paul" last="Fraser">Paul Fraser</name><name sortKey="Kawarai, Toshitaka" sort="Kawarai, Toshitaka" uniqKey="Kawarai T" first="Toshitaka" last="Kawarai">Toshitaka Kawarai</name><name sortKey="St George Hyslop, Peter" sort="St George Hyslop, Peter" uniqKey="St George Hyslop P" first="Peter" last="St George-Hyslop">Peter St George-Hyslop</name><name sortKey="Tandon, Anurag" sort="Tandon, Anurag" uniqKey="Tandon A" first="Anurag" last="Tandon">Anurag Tandon</name><name sortKey="Westaway, David" sort="Westaway, David" uniqKey="Westaway D" first="David" last="Westaway">David Westaway</name></noCountry><country name="Canada"><region name="Ontario"><name sortKey="Wislet Gendebien, Sabine" sort="Wislet Gendebien, Sabine" uniqKey="Wislet Gendebien S" first="Sabine" last="Wislet-Gendebien">Sabine Wislet-Gendebien</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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