Pathogenesis of parkinson's disease: dopamine, vesicles and α-synuclein

Lotharius, Julie; Brundin, Patrik

doi:10.1038/nrn983

Cited by 1,152 publications

(892 citation statements)

References 127 publications

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“…It is caused by the degeneration of dopaminergic neurons in the substantia nigra pars compacta leading to significant depletion in dopamine (Lotharius and Brundin, 2002;Siderowf and Stern, 2003;Alexander, 2004). Parkinson disease is characterized by lack of coordination of voluntary movements leading to skeletal muscle abnormalities (Berardelli et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Apoptotic Mediators are Upregulated in the Skeletal Muscle of Chronic/Progressive Mouse Model of Parkinson's Disease

Erekat

2015

The Anatomical Record

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Apoptosis has been implicated in the pathogenesis of Parkinson disease (PD). Parkinson disease is characterized by skeletal muscle abnormalities. The aim of this study is to illustrate the impact of PD induction on the expression of apoptotic mediators. Twenty normal albino mice were randomly selected and equally divided in control and PD groups. Chronic Parkinsonism was induced in the PD group using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTP/p). After that, samples from gastrocnemius muscles were evaluated by immunohistochemistry to examine the expression of p53 and active caspase-3 in the two groups of animals. P53 and active caspase-3 expression was significantly higher in gastrocnemius skeletal muscle in PD mice compared with that in the control mice (P value <0.01). Furthermore, we show PD gastrocnemius muscle atrophy measured by significant reduction (P < 0.01) in the muscle fiber cross-sectional area. Thus, our present data suggest that PD induction increased the expression of the apoptotic mediators p53 and active caspase-3 in gastrocnemius muscle, indicating the induction of apoptosis, which was correlative with gastrocnemius muscle atrophy subsequent to the induction of PD.

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Section: Introductionmentioning

confidence: 99%

Apoptotic Mediators are Upregulated in the Skeletal Muscle of Chronic/Progressive Mouse Model of Parkinson's Disease

Erekat

2015

The Anatomical Record

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“…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] . One theory suggested that -synuclein might be linked to PD via the regulation of dopamine (DA) homeostasis [19][20][21][22][23] .…”

Section: Introductionmentioning

confidence: 99%

“…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] . One theory suggested that -synuclein might be linked to PD via the regulation of dopamine (DA) homeostasis [19][20][21][22][23] . Several studies have proposed that -synuclein may be involved in regulating the biosynthesis, vesicles storage and release, as well as reuptake of DA [24][25][26][27][28][29][30][31] .…”

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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“…15−18 In line with this concept, it has been proposed that changes in α-Syn homeostasis upon aging result in an apparent increase of the cellular α-Syn concentration. This may include, for instance, alterations in the molecular crowding state due to cell shrinkage 2,19 or a breakdown of the α-Syn degradation mechanism. 20,21 Recent studies highlighted the enhanced aggregation propensity of α-Syn in the presence of interfaces such as lipid bilayers 22,23 or suggest a surface-assisted nucleation mechanism.…”

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confidence: 99%

On-Surface Aggregation of α-Synuclein at Nanomolar Concentrations Results in Two Distinct Growth Mechanisms

Rabe

Soragni

Reynolds

et al. 2013

ACS Chem. Neurosci.

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The aggregation of α-synuclein (α-Syn) is believed to be one of the key steps driving the pathology of Parkinson's disease and related neurodegenerative disorders. One of the present hypotheses is that the onset of such pathologies is related to the rise of α-Syn levels above a critical concentration at which toxic oligomers or mature fibrils are formed. In the present study, we find that α-Syn aggregation in vitro is a spontaneous process arising at bulk concentrations as low as 1 nM and below in the presence of both hydrophilic glass surfaces and cell membrane mimicking supported lipid bilayers (SLBs). Using three-dimensional supercritical angle fluorescence (3D-SAF) microscopy, we observed the process of α-Syn aggregation in situ. As soon as α-Syn monomers were exposed to the surface, they started to adsorb and aggregate along the surface plane without a prior lag phase. However, at a later stage of the aggregation process, a second type of aggregate was observed. In contrast to the first type, these aggregates showed an extended structure being tethered with one end to the surface and being mobile at the other end, which protruded into the solution. While both types of α-Syn aggregates were found to contain amyloid structures, their growing mechanisms turned out to be significantly different. Given the clear evidence that surface-induced α-Syn aggregation in vitro can be triggered at bulk concentrations far below physiological concentrations, the concept of a critical concentration initiating aggregation in vivo needs to be reconsidered.

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Pathogenesis of parkinson's disease: dopamine, vesicles and α-synuclein

Cited by 1,152 publications

References 127 publications

Apoptotic Mediators are Upregulated in the Skeletal Muscle of Chronic/Progressive Mouse Model of Parkinson's Disease

Apoptotic Mediators are Upregulated in the Skeletal Muscle of Chronic/Progressive Mouse Model of Parkinson's Disease

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

On-Surface Aggregation of α-Synuclein at Nanomolar Concentrations Results in Two Distinct Growth Mechanisms

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