Multiple-system atrophy: a new α-synuclein disease?

Gai, Wei-Ping; Power, John H.; Blumbergs, Peter; Blessing, W.W.

doi:10.1016/s0140-6736(05)79256-4

Cited by 227 publications

(117 citation statements)

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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). 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)(16)(17)(18).…”

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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.

410

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.

410

452

View full text Add to dashboard Cite

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“…The group of synucleinopathies comprises many neurodegenerative diseases, among which the best known and most common is PD, but it also includes Lewy body dementia, multiple system atrophy, neurodegeneration with brain iron accumulation type I, diffuse Lewy body disease, and Lewy body variant of Alzheimer's disease (Arawaka et al, 1998;Gai et al, 1998;Spillantini et al, 1997;Wakabayashi et al, 1997). These are all brain amyloidoses with the common characteristic of pathological intracellular inclusions of aggregates that havesynuclein as the key component (Spillantini et al, 1997;Wakabayashi et al, 1997).…”

Section: Synucleinopathiesmentioning

confidence: 99%

Alpha-Synuclein Interactions with Membranes

Pirc¹,

Ulrih²

2011

Etiology and Pathophysiology of Parkinson's Disease

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“…Three autosomal dominant missense mutations of a-synuclein (A30P, A53T, and E46K) have been linked to an inherited form of PD that shows all the neuropathological characteristics of PD (Polymeropoulos et al, 1997;Kruger et al, 1998;Zarranz et al, 2004). a-Synuclein is a major constituent of the intracellular aggregates found in the Lewy body of PD and in glial cytoplasmic inclusions of multiple system atrophy (MSA) (Spillantini et al, 1997;Gai et al, 1998).…”

Section: Introductionmentioning

confidence: 99%