Immunoelectron-microscopic demonstration of NACP/α-synuclein-epitopes on the filamentous component of Lewy bodies in Parkinson's disease and in dementia with Lewy bodies

Arima, Kunimasa; Uéda, Kenji; Sunohara, Nobuhiko; Hirai, Shinobu; Izumiyama, Yoko; Tonozuka-Uehara, Haruko; Kawai, Mitsuru

doi:10.1016/s0006-8993(98)00734-3

Cited by 235 publications

(153 citation statements)

References 17 publications

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“…They noted perikaryal threads, which were a loose mesh-work of small bundles of filaments immunoreactive for ␣-SYN but not for ubiquitin (dystrophic neurites were identified by antisera to both ␣-SYN and ubiquitin). The ultrastructural features of the filaments in LB, pale bodies, and perikaryal threads were similar, and Arima et al (31) hypothesized that the ␣-SYN perikaryal threads represent an early stage of filament assembly that may develop into LB or pale bodies. Although ␣-SYN and ubiquitin are major components of LB, a large number of other constituents, such as neurofilaments, have been reported in LB (see Supporting List, which is published as supporting information on the PNAS web site).…”

Section: Description and Composition Of Lb Light Microscopymentioning

confidence: 91%

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Lewy bodies

Shults

2006

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

402

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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Section: Description and Composition Of Lb Light Microscopymentioning

confidence: 91%

“…The study of the ultrastructure of ␣-SYN in LB was carried out by Arima et al (31). They noted ␣-SYN filaments in LB, pale bodies, and perikaryal threads.…”

Section: Description and Composition Of Lb Light Microscopymentioning

confidence: 99%

Lewy bodies

Shults

2006

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

402

277

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“…Previous studies have shown that -synuclein mutations (A53T, A30P, E46K) or triplications are associated with some autosomal-dominant PD [3][4][5][6] . Although there is no -synuclein gene mutation identified in idiopathic PD [7,8] , aggregated -synuclein has been found to be the major component of Lewy bodies and Lewy neurites, the pathological hallmarks of PD [9][10][11][12][13][14] . Although the normal function ofsynuclein and its role in the pathogenesis of PD remain unclear, several hypotheses have been proposed based on its physical properties or interacting partners [15][16][17][18][19][20][21] .…”

Section: Introductionmentioning

confidence: 99%

RNA interference mediated silencing of α-synuclein in MN9D cells and its effects on cell viability

et al. 2008

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ObjectiveTo silence the expression of -synuclein in MN9D dopaminergic cells using vector mediated RNA interference (RNAi) and examined its effects on cell proliferation and viability. Methods We identified two 19-nucleotide stretches within the coding region of the -synuclein gene and designed three sets of oligonucleotides to generate doublestranded (ds) oligos. The ds oligos were inserted into the pENTR TM /H1/TO vector and transfected into MN9D dopaminergic cells. -Synuclein expression was detected by RT-PCR, real-time PCR, immunocytochemistry staining and Western blot. In addition, we measured cell proliferation using growth curves and cell viability by 3-(4, 5)-dimethylthiahiazo (-z-y1)-3, 5-diphenytetrazoliumromide (MTT). Results The mRNA and protein levels of -synuclein gene were significantly down-regulated in pSH2/ -SYN-transfected cells compared with control MN9D and pSH/CON-transfected MN9D cells, while pSH1/ -SYNtransfected cells showed no significant difference. Silencing -synuclein expression does not affect cell proliferation but may decrease cell viability. Conclusion Our results demonstrated pSH2/ -SYN is an effective small interfering RNA (siRNA) sequence and potent silencing of mouse -synuclein expression in MN9D cells by vector-based RNAi, which provides the tools for studying the normal function of -synuclein and examining its role in Parkinson's disease (PD) pathogenesis.-Synuclein may be important for the viability of MN9D cells, and loss of -synuclein may induce cell injury directly or indirectly.

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“…The fibrillar core contains synuclein (18,19). LBs are seen in sporadic and familial PD, and in vitro evidence exists that PD-associated synuclein mutations increase the rate of synuclein fibrilization (20 -23).…”

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confidence: 99%

Parkinson's Disease-associated α-Synuclein Is a Calmodulin Substrate

Martinez

Moeller

Erdjument‐Bromage

et al. 2003

Journal of Biological Chemistry

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␣-Synuclein is a neuronal protein thought to be central in the pathogenesis of Parkinson's disease (PD) because it comprises the fibrillar core of Lewy bodies, one of the histologically defining lesions of PD, and because mutations in ␣-synuclein cause autosomal dominant PD. Although its physiologic role is uncertain, ␣-synuclein is a synaptic protein that may contribute to plasticity. We produced synuclein with incorporated photoprobes to identify and purify novel synuclein-interacting proteins both to begin to clarify the physiology of synuclein and to identify factors that may regulate synuclein conformation. We detected several cross-links and purified and identified one as calmodulin (CaM). CaM binds to both wild type and PD-associated mutant ␣-synucleins in a calcium-dependent manner. We further demonstrate that CaM and ␣-synuclein interact in intact cells in a calcium-dependent manner and that activated CaM accelerates the formation of synuclein fibrils in vitro. We hypothesize that the known calcium control of synuclein function is mediated through CaM interaction and that CaM potentially alters synuclein conformation.

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Immunoelectron-microscopic demonstration of NACP/α-synuclein-epitopes on the filamentous component of Lewy bodies in Parkinson's disease and in dementia with Lewy bodies

Cited by 235 publications

References 17 publications

Lewy bodies

Lewy bodies

RNA interference mediated silencing of α-synuclein in MN9D cells and its effects on cell viability

Parkinson's Disease-associated α-Synuclein Is a Calmodulin Substrate

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