Cytosolic proteins regulate alpha-synuclein dissociation from presynaptic membranes.
Identifieur interne : 002A30 ( Main/Merge ); précédent : 002A29; suivant : 002A31Cytosolic 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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pubmed:16926154Le document en format XML
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<term>Mice, Transgenic</term>
<term>Parkinson Disease (genetics)</term>
<term>Parkinson Disease (metabolism)</term>
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<term>Proteins (genetics)</term>
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<term>Synaptic Membranes (metabolism)</term>
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<term>Temperature</term>
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<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>
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