Causal relation between α-synuclein locus duplication as a cause of familial Parkinson's disease

Ibáñez, Pablo; Bonnet, Anne Marie; Débarges, B; Lohmann, Ebba; Tison, François; Agid, Yves; Dürr, Alexandra; Brice, Alexis; Pollak, Pierre

doi:10.1016/s0140-6736(04)17104-3

Cited by 962 publications

(403 citation statements)

References 5 publications

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“…other neurodegenerative disorders (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). α-Synuclein is largely cytosolic, but readily binds to membranes, and associates with synaptic vesicles in the presynaptic terminal (22,23).…”

Section: α-Synuclein Multimerizes On Phospholipid Surfaces In An Antimentioning

confidence: 99%

“…Point mutations in α-synuclein (A30P, E46K, H50Q, G51D, and A53T) as well as α-synuclein gene duplications and triplications produce early-onset Parkinson's disease (PD) (4)(5)(6)(7)(8)(9)(10). Moreover, α-synuclein is a major component of intracellular protein aggregates called Lewy bodies, which are pathological hallmarks of neurodegenerative disorders such as PD, Lewy body dementia, and multiple system atrophy (11)(12)(13)(14).…”

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confidence: 99%

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α-Synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation

Burré¹,

Sharma²,

Südhof

2014

Proc. Natl. Acad. Sci. U.S.A.

419

452

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Physiologically, α-synuclein chaperones soluble NSF attachment protein receptor (SNARE) complex assembly and may also perform other functions; pathologically, in contrast, α-synuclein misfolds into neurotoxic aggregates that mediate neurodegeneration and propagate between neurons. In neurons, α-synuclein exists in an equilibrium between cytosolic and membrane-bound states. Cytosolic α-synuclein appears to be natively unfolded, whereas membrane-bound α-synuclein adopts an α-helical conformation. Although the majority of studies showed that cytosolic α-synuclein is monomeric, it is unknown whether membrane-bound α-synuclein is also monomeric, and whether chaperoning of SNARE complex assembly by α-synuclein involves its cytosolic or membrane-bound state. Here, we show using chemical cross-linking and fluorescence resonance energy transfer (FRET) that α-synuclein multimerizes into large homomeric complexes upon membrane binding. The FRET experiments indicated that the multimers of membrane-bound α-synuclein exhibit defined intermolecular contacts, suggesting an ordered array. Moreover, we demonstrate that α-synuclein promotes SNARE complex assembly at the presynaptic plasma membrane in its multimeric membrane-bound state, but not in its monomeric cytosolic state. Our data delineate a folding pathway for α-synuclein that ranges from a monomeric, natively unfolded form in cytosol to a physiologically functional, multimeric form upon membrane binding, and show that only the latter but not the former acts as a SNARE complex chaperone at the presynaptic terminal, and may protect against neurodegeneration.Parkinson's disease | synapse | SNARE proteins | membrane fusion α -Synuclein is an abundant presynaptic protein that physiologically acts to promote soluble NSF attachment protein receptor (SNARE) complex assembly in vitro and in vivo (1-3). Point mutations in α-synuclein (A30P, E46K, H50Q, G51D, and A53T) as well as α-synuclein gene duplications and triplications produce early-onset Parkinson's disease (PD) (4-10). Moreover, α-synuclein is a major component of intracellular protein aggregates called Lewy bodies, which are pathological hallmarks of neurodegenerative disorders such as PD, Lewy body dementia, and multiple system atrophy (11-14). Strikingly, neurotoxic α-synuclein aggregates propagate between neurons during neurodegeneration, suggesting that such α-synuclein aggregates are not only intrinsically neurotoxic but also nucleate additional fibrillization (15-18).α-Synuclein is highly concentrated in presynaptic terminals where α-synuclein exists in an equilibrium between a soluble and a membrane-bound state, and is associated with synaptic vesicles (19)(20)(21)(22). The labile association of α-synuclein with membranes (23, 24) suggests that binding of α-synuclein to synaptic vesicles, and its dissociation from these vesicles, may regulate its physiological function. Membrane-bound α-synuclein assumes an α-helical conformation (25-32), whereas cytosolic α-synuclein is natively unfolded and monomeric (refs. 25, 2...

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Section: α-Synuclein Multimerizes On Phospholipid Surfaces In An Antimentioning

confidence: 99%

mentioning

confidence: 99%

α-Synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation

Burré¹,

Sharma²,

Südhof

2014

Proc. Natl. Acad. Sci. U.S.A.

419

452

View full text Add to dashboard Cite

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“…Proteomic analysis and functional studies have identified a number of proteins that interact with DAT to regulate its activity and its membrane distribution, one being ␣-synuclein (8 -11). Although the exact stoichiometry of DAT and ␣-synuclein interaction is not known, by using the yeast two-hybrid system, Lee et al (12) first demonstrated that DAT directly interacts with ␣-synuclein, a neuronal protein enriched at presynaptic terminals (13,14) implicated in neurodegenerative diseases (15)(16)(17)(18) and drug addiction (19,20).…”

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confidence: 99%

Dopamine Transporter Activity Is Modulated by α-Synuclein

Butler

Goodwin

Saha

et al. 2015

Journal of Biological Chemistry

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Background: DAT regulates dopamine neurotransmission in the brain. Results: ␣-Synuclein influences DA efflux and membrane microdomain distribution of DAT. Conclusion: DAT activation recruits ␣-synuclein to the membrane, which in turn influences dopamine neurotransmission. Significance: Understanding the mechanisms associated with ␣-synuclein regulation of DAT may reveal disease-modifying targets for the treatment of pathologies associated with DA dysregulation.

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“…Formation of punctate cytoplasmic protein aggregates, known as Lewy bodies in dopaminergic neurons, is a pathological hallmark of PD 4 (1, 2). ␣Syn is a major component of Lewy bodies in which ␣Syn deposits as ␤-sheet-rich fibrils (1).…”

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confidence: 99%

“…␣Syn is a major component of Lewy bodies in which ␣Syn deposits as ␤-sheet-rich fibrils (1). Genetically, ␣Syn gene duplication (3,4), triplication (5), and missense mutations (6 -8) were found to cause earlyonset familial PD, which provide a direct genetic link between the ␣Syn gene and PD pathogenesis. Studies have found that the PD-causing ␣Syn mutations that lead to single amino acid substitution as A30P, E46K, and A53T accelerate ␣Syn aggregation into either oligomers or fibrils in vitro (9 -13).…”

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confidence: 99%

Residue Histidine 50 Plays a Key Role in Protecting α-Synuclein from Aggregation at Physiological pH

Chi

Armstrong

Jones

et al. 2014

Journal of Biological Chemistry

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Background: Mutations of ␣-synuclein (␣Syn) can cause early-onset familial Parkinson disease (PD). Results: The H50Q, H50D, or H50A substitution promotes, whereas the H50R substitution inhibits, ␣Syn aggregation in vitro. Conclusion:The recently identified PD-causing ␣Syn mutant, ␣Syn(H50Q), accelerates ␣Syn aggregation. Significance: The partial positive charge of His-50 at physiological pH likely plays a role in suppressing ␣Syn aggregation.

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Causal relation between α-synuclein locus duplication as a cause of familial Parkinson's disease

Cited by 962 publications

References 5 publications

α-Synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation

α-Synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation

Dopamine Transporter Activity Is Modulated by α-Synuclein

Residue Histidine 50 Plays a Key Role in Protecting α-Synuclein from Aggregation at Physiological pH

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