Decreased reuptake of dopamine in the dorsal striatum in the absence of alpha-synuclein

Chadchankar, Heramb; Ihalainen, Jouni; Tanila, Heikki; Yavich, Leonid

doi:10.1016/j.brainres.2011.01.064

Cited by 59 publications

(52 citation statements)

References 43 publications

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“…MPP + , the toxic metabolite of MPTP, is a substrate for the dopamine transporter (DAT), resulting in its selective uptake into dopaminergic terminals (30). Loss of α-synuclein has been reported to decrease cell surface expression of DAT in Snca -/-mice (31,32) and cultured cells (33), which might attenuate MPTP toxicity by altering MPP + uptake. However, studies showing that some strains of Snca -/-mice were protected against MPTP did not reveal any alteration in striMultiple convergent lines of evidence implicate both α-synuclein (encoded by SCNA) and mitochondrial dysfunction in the pathogenesis of sporadic Parkinson's disease (PD).…”

Section: Introductionmentioning

confidence: 99%

shRNA targeting α-synuclein prevents neurodegeneration in a Parkinson’s disease model

et al. 2015

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Section: Introductionmentioning

confidence: 99%

shRNA targeting α-synuclein prevents neurodegeneration in a Parkinson’s disease model

et al. 2015

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“…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][9][10][11][12][13][14][15][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%.…”

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confidence: 99%

“…Studies in cell culture point to α-synuclein as a possible mediator of these early changes, including effects on DA synthesis, storage and release (7)(8)(9), and vesicular trafficking (9,10). In vivo studies performed in α-synuclein knockout mice, moreover, have shown that α-synuclein plays a role in the regulation of transmitter storage and release in DA neurons (11)(12)(13), suggesting that the synaptic release machinery may be an important target for α-synuclein-induced toxicity.…”

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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

229

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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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“…It might be due to compensatory increases in different dopaminergic regions. Interestingly, Chadchankar et al (2011) show increased extracellular DA levels in the striatum of alphasynuclein deficient mice, indicating that compensatory mechanisms within the nigrostriatal system are taking place in different experimental approximations to PD. Moreover, the number of TH-positive neurons shows a trend to increase in the ApoD-KO SNc in control condition (Fig.…”

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Apolipoprotein D mediates autocrine protection of astrocytes and controls their reactivity level, contributing to the functional maintenance of paraquat-challenged dopaminergic systems

Bajo‐Grañeras¹,

Ganfornina²,

Martín-Tejedor³

et al. 2011

Glia

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The study of glial derived factors induced by injury and degeneration is important to understand the nervous system response to deteriorating conditions. We focus on Apolipoprotein D (ApoD), a Lipocalin expressed by glia and strongly induced upon aging, injury or neurodegeneration.Here we study ApoD function in the brain of wild type and ApoD-KO mice by combining in vivo experiments with astrocyte cultures. Locomotor performance, dopamine concentration, and gene expression levels in the substantia nigra were assayed in mice treated with paraquat (PQ). The regulation of ApoD transcription, a molecular screening of oxidative stress (OS)-related genes, cell viability and oxidation status, and the effects of adding human ApoD were tested in astrocyte cultures. We demonstrate that (1) ApoD is required for an adequate locomotor performance, modifies the gene expression profile of PQ-challenged nigrostriatal system, and contributes to its functional maintenance; (2) ApoD expression in astrocytes is controlled by the OSresponsive JNK pathway; (3) ApoD contributes to an autocrine protecting mechanism in astrocytes, avoiding peroxidated lipids accumulation and altering the PQ transcriptional response of genes involved in ROS managing and the inflammatory response to OS; (4) Addition of human ApoD to ApoD-KO astrocytes promotes survival through a mechanism accompanied by protein internalization and modulation of astroglial reactivity. Our data support that ApoD contributes to the endurance of astrocytes and decreases their reactivity level in vitro and in vivo. ApoD function as a maintenance factor for astrocytes would suffice to explain the observed protection by ApoD of OS-vulnerable dopaminergic circuits in vivo. V

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Decreased reuptake of dopamine in the dorsal striatum in the absence of alpha-synuclein

Cited by 59 publications

References 43 publications

shRNA targeting α-synuclein prevents neurodegeneration in a Parkinson’s disease model

shRNA targeting α-synuclein prevents neurodegeneration in a Parkinson’s disease model

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

Apolipoprotein D mediates autocrine protection of astrocytes and controls their reactivity level, contributing to the functional maintenance of paraquat-challenged dopaminergic systems

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