Synuclein modulation of monoamine transporters

Oaks, Adam W.; Sidhu, Anita

doi:10.1016/j.febslet.2011.03.009

Cited by 67 publications

(66 citation statements)

References 53 publications

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“…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: 81%

“…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: 81%

See 1 more Smart Citation

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.

252

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: 81%

Section: Discussionsupporting

confidence: 81%

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.

252

221

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“…In addition, the pathologic process in idiopathic PD and related movement disorders is characterized by accumulation of a-synuclein within the nigrostriatal pathways. Finally, reduced levels of DAT indirectly reflect degeneration of nigrostriatal neurons (12)(13)(14)(15). Over the years, several radioligands have been developed for PET imaging of the DAT, although only a few of them qualify for broad clinical application based on possible radiolabeling with 18 F and optimal kinetic properties (16).…”

mentioning

confidence: 99%

Quantitative Analysis of ¹⁸F-(E)-N-(3-Iodoprop-2-Enyl)-2β-Carbofluoroethoxy-3β-(4′-Methyl-Phenyl) Nortropane Binding to the Dopamine Transporter in Parkinson Disease

et al. 2015

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nortropane ( 18 F-FE-PE2I) is a recently developed radioligand for the in vivo quantification of the dopamine transporter (DAT) in the striatum and substantia nigra (SN). The aim of this study was to examine the suitability of 18 F-FE-PE2I as a tool for imaging the nigrostriatal pathway in Parkinson disease (PD) with PET. Methods: Ten PD patients (9 men and 1 woman; mean age ± SD, 60 ± 9 y; Hoehn and Yahr, 1-2; Unified Parkinson Disease Rating Scale motor, 18.9 ± 6.7) and 10 controls (9 men and 1 woman; mean age ± SD, 60 ± 7 y) were included. PET measurements with 18 F-FE-PE2I were conducted for 93 min using the High-Resolution Research Tomograph. Venous blood was drawn to compare protein binding, parent fraction, and radiometabolite composition in PD patients and controls. Regions of interest for the caudate, putamen, ventral striatum, SN, and cerebellum were drawn on coregistered MR images. The outcome measure was the binding potential (BP ND ) estimated with the simplified reference tissue model and the Logan graphical analysis, using the cerebellum as a reference region. Time stability of BP ND was examined to define the shortest acquisition protocol for quantitative studies. The wavelet-aided parametric imaging method was used to obtain high-resolution BP ND images to compare DAT availability in the striatum and SN in PD patients and control subjects. Group differences were assessed with the unpaired t test (P , 0.05). Results: Parent, radiometabolite fractions, plasma concentration, and cerebellar uptake of 18 F-FE-PE2I did not differ significantly between PD patients and controls. Stable estimates of BP ND (,8% of the 93-min value) were obtained with the simplified reference tissue model using approximately 66 min of data. BP ND values in PD patients were significantly lower than those in controls (P , 0.05) in the caudate (2.54 ± 0.79 vs. 3.68 ± 0.56), putamen (1.39 ± 1.04 vs. 4.41 ± 0.54), ventral striatum (2.26 ± 0.93 vs. 3.30 ± 0.46), and SN (0.46 ± 0.20 vs. 0.68 ± 0.15). Conclusion: 18 F-FE-PE2I is clearly a suitable radioligand for DAT quantification and imaging of the nigrostriatal pathway in PD. Similar metabolism in controls and PD patients, suitability of the cerebellum as a reference region, and accuracy of quantification using approximately 66 min of PET data are advantages for noninvasive and simplified imaging protocols for PD studies. Finally, DAT loss in PD can be measured in both the striatum and the SN, supporting the utility of 18 F-FE-PE2I as an imaging tool of the nigrostriatal pathway.

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“…Interestingly, several recent reports suggest that synuclein proteins have a critical role in monoamine neurotransmitter homeostasis. In addition, the physical interactions between synuclein proteins and monoamine transporters (DA, serotonin (5HT) and norepinephrine (NE) transporters) indicate an important role for the synucleins in regulating transporter function, trafficking and distribution at the DA, 5HT and NE synapses (for review see Oaks and Sidhu, 2011).…”

Section: Dopamine Transporter and Neural Plasticitymentioning

confidence: 99%

Addictive Drugs and Synaptic Plasticity

Negrete-Díaz¹,

Flores²,

Sihra³

et al. 2012

Addictions - From Pathophysiology to Treatment

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Synuclein modulation of monoamine transporters

Cited by 67 publications

References 53 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

Quantitative Analysis of ¹⁸F-(E)-N-(3-Iodoprop-2-Enyl)-2β-Carbofluoroethoxy-3β-(4′-Methyl-Phenyl) Nortropane Binding to the Dopamine Transporter in Parkinson Disease

Addictive Drugs and Synaptic Plasticity

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Synuclein modulation of monoamine transporters

Cited by 67 publications

References 53 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

Quantitative Analysis of 18F-(E)-N-(3-Iodoprop-2-Enyl)-2β-Carbofluoroethoxy-3β-(4′-Methyl-Phenyl) Nortropane Binding to the Dopamine Transporter in Parkinson Disease

Addictive Drugs and Synaptic Plasticity

Contact Info

Product

Resources

About

Quantitative Analysis of ¹⁸F-(E)-N-(3-Iodoprop-2-Enyl)-2β-Carbofluoroethoxy-3β-(4′-Methyl-Phenyl) Nortropane Binding to the Dopamine Transporter in Parkinson Disease