Cytosolic proteins regulate alpha-synuclein dissociation from presynaptic membranes.
Identifieur interne : 002745 ( Main/Exploration ); précédent : 002744; suivant : 002746Cytosolic 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
Affiliations:
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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></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2006">2006</date><idno type="RBID">pubmed:16926154</idno><idno type="pmid">16926154</idno><idno 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dissociation from presynaptic membranes.</title><author><name sortKey="Wislet Gendebien, Sabine" sort="Wislet Gendebien, Sabine" uniqKey="Wislet Gendebien S" first="Sabine" last="Wislet-Gendebien">Sabine Wislet-Gendebien</name><affiliation wicri:level="4"><nlm:affiliation>Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen's 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><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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