NACP, a presynaptic protein, immunoreactivity in Lewy bodies in Parkinson's disease

Wakabayashi, Keiji; Matsumoto, Kayo; Takayama, Kiyoshi; Yoshimoto, Makoto; Takahashi, Hitoshi

doi:10.1016/s0304-3940(97)00891-4

Cited by 297 publications

(181 citation statements)

References 12 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). 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.

418

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.

418

452

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“…Attention focused on ␣-SYN when Polymeropoulos et al (6) reported that in a kindred with familial PD, a mutation, A53T, was associated with disease. A number of groups quickly reported that ␣-SYN is a major component of LB (41)(42)(43)(44)(45). Two additional missense mutations, A30P (46) and E46K (47), are also associated with familial PD.…”

Section: ␣-Syn a Major Component Of Lbmentioning

confidence: 99%

Lewy bodies

Shults

2006

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

408

277

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Lewy bodies (LB) in the substantia nigra are a cardinal pathological feature of Parkinson's disease, but they occur in a number of neurodegenerative diseases and can be widespread in the nervous system. The characteristics, locations, and composition of LB are reviewed, with particular attention to ␣-synuclein (␣-SYN), which appears to be the major component of LB. The propensity for ␣-SYN, a presynaptic protein widely expressed in the brain, to aggregate is because of an amyloidogenic central region. The factors that favor the aggregation of ␣-SYN and mechanisms of toxicity are examined, and a mechanism through which aggregates of ␣-SYN could induce mitochondrial dysfunction and͞or release of proapoptotic molecules is proposed.

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“…Significantly, these lesions are pathological hallmarks of PD and DLB (13,14). Subsequent studies confirmed that normal, truncated, and aggregated ␣-synuclein are major components of LBs and Lewy neurites and that antibodies to ␣-synuclein are the most reliable and consistent immunological probes for detecting these lesions in situ (15)(16)(17)(18)(19). More recently, ␣-synuclein was also shown to be a prominent component of glial cell inclusions (GCIs) and neuronal cytoplasmic inclusions (NCIs) that are characteristic of multisystem atrophy (MSA) and Hallervorden-Spatz disease (20 -24).…”

mentioning

confidence: 97%

Mutant and Wild Type Human α-Synucleins Assemble into Elongated Filaments with Distinct Morphologies in Vitro

Giasson¹,

Uryu

Trojanowski

et al. 1999

Journal of Biological Chemistry

497

392

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NACP, a presynaptic protein, immunoreactivity in Lewy bodies in Parkinson's disease

Cited by 297 publications

References 12 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

Lewy bodies

Mutant and Wild Type Human α-Synucleins Assemble into Elongated Filaments with Distinct Morphologies in Vitro

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