$alpha;-Synuclein regulation of the dopaminergic transporter: a possible role in the pathogenesis of Parkinson's disease

Sidhu, Anita

doi:10.1016/s0014-5793(04)00331-x

Cited by 59 publications

(99 citation statements)

References 46 publications

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“…Interestingly, the expression of the DAT protein in axons and terminals was maintained in the surviving DA innervation at all time points, suggesting that the effect seen on DA reuptake is due to impaired function, rather than an actual loss, of the DAT protein. This is in line with previous observations made in α-synucleinoverexpressing cell lines, showing that increased levels of α-synuclein induce a dose-dependent reduction in DAT function and that this effect is mediated via an increased trafficking of the transporter away from the cell surface without any change in the DAT expression level (21,22) On the basis of these in vitro studies it seems likely that the impairment in DA reuptake seen here is due to an internalization of DAT leading to a reduced capacity for transport of DA across the membrane.…”

Section: Discussionsupporting

confidence: 93%

“…These data are consistent with previous studies showing that the synuclein family of proteins are likely to play a role both in normal physiological neurotransmitter release (11,12,19,20) and in the regulation of transporter function (21,22). In vitro studies have shown that overexpression of α-synuclein inhibits the release of catecholamines from adrenal chromaffin and PC12 cells, probably owing to a reduced pool of readily releasable vesicles (9).…”

Section: Discussionsupporting

confidence: 92%

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Impaired neurotransmission caused by overexpression of α-synuclein in nigral dopamine neurons

Lundblad

Decressac

Mattsson

et al. 2012

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

258

221

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We used in vivo amperometry to monitor changes in synaptic dopamine (DA) release in the striatum induced by overexpression of human wild-type α-synuclein in nigral DA neurons, induced by injection of an adeno-associated virus type 6 (AAV6)-α-synuclein vector unilaterally into the substantia nigra in adult rats. Impairments in DA release evolved in parallel with the development of degenerative changes in the nigrostriatal axons and terminals. The earliest change, seen 10 d after vector injection, was a marked, ≈50%, reduction in DA reuptake, consistent with an early dysfunction of the DA transporter that developed before any overt signs of axonal damage. At 3 wk, when the first signs of axonal damage were observed, the amount of DA released after a KCl pulse was reduced by 70-80%, and peak DA concentration was delayed, indicating an impaired release mechanism. At later time points, 8-16 wk, overall striatal innervation density was reduced by 60-80% and accompanied by abundant signs of axonal damage in the form of α-synuclein aggregates, axonal swellings, and dystrophic axonal profiles. At this stage DA release and reuptake were profoundly reduced, by 80-90%. The early changes in synaptic DA release induced by overexpression of human α-synuclein support the idea that early predegenerative changes in the handling of DA may initiate, and drive, a progressive degenerative process that hits the axons and terminals first. Synaptic dysfunction and axonopathy would thus be the hallmark of presymptomatic and earlystage Parkinson disease, followed by neuronal degeneration and cell loss, characteristic of more advanced stages of the disease.neurodegeneration | synaptic transmission I n Parkinson disease (PD) damage to axons and axonal terminals is likely to precede any overt dopamine (DA) neuron cell death, suggesting that the disease process may start at the axon terminal level and progress retrogradely to affect the cell bodies. Support of this idea comes from autopsy studies of brains from PD patients, which suggest that the extent of damage to the DA terminals in caudate nucleus and putamen at the time of disease onset is more extensive than the loss of DA neurons in the substantia nigra (see ref. 1 for a recent review). Although genuine longitudinal data are difficult to obtain in human material, available postmortem data indicate that the loss of DA in the caudate nucleus at the time of onset of symptoms is on the order of 70-80%, whereas as much as 70% of the nigral DA cell bodies may still be alive (1-5). Measurement of binding to the vesicular monoamine transporter (VMAT), which is likely to be a good measure of the functional integrity of the DA terminals, has shown severe loss of VMAT in the caudate nucleus early in the disease in some patients (6).Together, these data suggest that impairments at the terminal/ synaptic level may be a prominent feature of presymptomatic and early-stage PD and that impaired DA neurotransmission may contribute to the functional deficits seen also at more advanced stages of the disea...

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 92%

Impaired neurotransmission caused by overexpression of α-synuclein in nigral dopamine neurons

Lundblad

Decressac

Mattsson

et al. 2012

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

258

221

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“…In animals lacking functional DAT-1, dopamine reuptake is blocked, presumably limiting the intraneuronal interaction between ␣-synuclein and dopamine, which may have subsequent consequences for degeneration. It is also possible that the neurodegeneration observed is attributable to the misregulation of direct interactions between ␣-synuclein and DAT-1, because wildtype ␣-synuclein has been shown to modulate DAT activity (Sidhu et al, 2004).…”

Section: How Do Torsins Protect Da Neurons Against Various Cellular Imentioning

confidence: 99%

Torsin-Mediated Protection from Cellular Stress in the Dopaminergic Neurons ofCaenorhabditis elegans

Cao¹,

Gelwix²,

Caldwell³

et al. 2005

J. Neurosci.

261

286

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Parkinson's disease (PD) is linked genetically to proteins that function in the management of cellular stress resulting from protein misfolding and oxidative damage. Overexpression or mutation of ␣-synuclein results in the formation of Lewy bodies and neurodegeneration of dopaminergic (DA) neurons. Human torsinA, mutations in which cause another movement disorder termed early-onset torsion dystonia, is highly expressed in DA neurons and is also a component of Lewy bodies. Previous work has established torsins as having molecular chaperone activity. Thus, we examined the ability of torsinA to manage cellular stress within DA neurons of the nematode Caenorhabditis elegans. Worm DA neurons undergo a reproducible pattern of neurodegeneration after treatment with 6-hydroxydopamine (6-OHDA), a neurotoxin commonly used to model PD. Overexpression of torsins in C. elegans DA neurons results in dramatic suppression of neurodegeneration after 6-OHDA treatment. In contrast, expression of either dystonia-associated mutant torsinA or combined overexpression of wild-type and mutant torsinA yielded greatly diminished neuroprotection against 6-OHDA. We further demonstrated that torsins seem to protect DA neurons from 6-OHDA through downregulating protein levels of the dopamine transporter (DAT-1) in vivo. Additionally, we determined that torsins protect robustly against DA neurodegeneration caused by overexpression of ␣-synuclein. Using mutant nematodes lacking DAT-1 function, we also showed that torsin neuroprotection from ␣-synuclein-induced degeneration occurs in a manner independent of this transporter. Together, these data have mechanistic implications for movement disorders, because our results demonstrate that torsin proteins have the capacity to manage sources of cellular stress within DA neurons.

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“…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] . In addition, -synuclein, as a chaperone, has been reported to interact with many other proteins, including 14-3-3, ERK1/2, parkin, etc.…”

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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$alpha;-Synuclein regulation of the dopaminergic transporter: a possible role in the pathogenesis of Parkinson's disease

Cited by 59 publications

References 46 publications

Impaired neurotransmission caused by overexpression of α-synuclein in nigral dopamine neurons

Impaired neurotransmission caused by overexpression of α-synuclein in nigral dopamine neurons

Torsin-Mediated Protection from Cellular Stress in the Dopaminergic Neurons ofCaenorhabditis elegans

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

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