α-Synuclein Gene Deletion Decreases Brain Palmitate Uptake and Alters the Palmitate Metabolism in the Absence of α-Synuclein Palmitate Binding

Golovko, Mikhail Y.; Færgeman, Nils J.; Cole, Nelson B.; Castagnet, P.I.; Nussbaum, Robert L.; Murphy, Eric J.

doi:10.1021/bi0502137

Cited by 101 publications

(143 citation statements)

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“…These results are consistent with those observed for uptake of 16:0 into brains lacking α-synuclein (29) and with its affect on 20:4n-6 and 16:0 uptake and metabolism in primary astrocytes (11). Brain cytosolic, unesterified polyunsaturated fatty acid mass is reduced when α-synuclein is absent (88), suggesting a connection between α-synuclein expression and polyunsaturated fatty acids.…”

Section: Discussionsupporting

confidence: 90%

“…The mouse surgery and tracer infusion was performed as previously described (29,46,47 (pH 7.4) buffer containing "essentially fatty acid free" bovine serum albumin (50 mg/ml, Sigma Chemical Co., St. Louis, MO). Awake (3-4 hours post-operative) fasted, male mice (Snca +/+ or Snca -/-) were infused with 170 μCi/kg of [1-14 C]20:4n-6 into the femoral vein over 10 min at a constant rate of 30 μL/min.…”

Section: Mouse Surgery and Tracer Infusionmentioning

confidence: 99%

“…Previously, we demonstrated that α-synuclein deficiency decreased brain 16:0 uptake in vivo (29) and reduced 16:0 and 20:4n-6 uptake in cultured astrocytes (11). We assessed the effect of α-synuclein on brain 20:4n-6 uptake in vivo by infusing Snca +/+ and Snca -/-mice with [1-14 C]20:4n-6 (i. v.).…”

Section: Absence Of α-Synuclein Reduced Brain 20:4n-6 Uptakementioning

confidence: 99%

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Acyl-CoA Synthetase Activity Links Wild-Type but Not Mutant α-Synuclein to Brain Arachidonate Metabolism

et al. 2006

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Because α-synuclein (Snca) has a role in brain lipid metabolism, we determined the impact that the loss of α-synuclein had on brain arachidonic acid (20:4n-6) metabolism in vivo using Snca -/-mice. We measured [1-14 C]20:4n-6 incorporation and turnover kinetics in brain phospholipids using an established steady-state kinetic model. Liver was used as a negative control and no changes were observed between groups. In Snca -/-brains, there was a marked reduction in 20:4n-6-CoA mass and in microsomal acyl-CoA synthetases (Acsl) activity toward 20:4n-6. Microsomal Acsl activity was completely restored after the addition of exogenous wt mouse or human α-synuclein, but not by A30P, E46K, and A53T forms of α-synuclein. Acsl and acyl-CoA hydrolase expression was not different between groups. The incorporation and turnover of 20:4n-6 into brain phospholipid pools was markedly reduced. The dilution coefficient lambda, which indicates 20:4n-6 recycling between the acyl-CoA pool and brain phospholipids, was increased 3.3-fold, indicating more 20:4n-6 was entering the 20:4n-6-CoA pool from the plasma relative to that being recycled from the phospholipids. This is consistent with the reduction in Acsl activity observed in the Snca -/-mice. Using titration microcalorimetry, we determined that α-synuclein bound free 20:4n-6 (K d of 3.7 μM), but did not bind 20:4n-6-CoA. These data suggest α-synuclein is involved in substrate presentation to Acsl rather than product removal. In summary, our data demonstrate that α-synuclein has a major role in brain 20:4n-6 metabolism through its modulation of endoplasmic reticulum localized acyl-CoA synthetase activity, although mutants forms of α-synuclein fail to restore this activity. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript α-Synuclein is a 140 amino acid soluble protein that is highly expressed in the central nervous system (1,2) and is abundant in presynaptic terminals of neurons (1,(3)(4)(5). α-Synuclein is also found in other regions of neurons, in astrocytes, and in oligodendroglia (6-11). Overexpression of and mutations in α-synuclein are associated with early onset Parkinson's disease (12)(13)(14)(15) and other neurodegenerative diseases (16)(17)(18)(19)(20). Despite this association with neurodegenerative diseases, the physiological function of this protein remains unclear.Several lines of evidence suggest that α-synuclein can influence brain lipid metabolism. It has structural similarities to class A2 apolipoproteins (21,22) and to fatty acid binding proteins (23), suggesting that α-synuclein may alter intracellular lipid trafficking, the regulation of lipid metabolism, and may act to stabilize lipid membranes. α-Synuclein binds to small phospholipid vesicles (22,24,25) and to brain vesicles (26). Consistent with this binding, the lack of α-synuclein decreases the resting/reserve pool of synaptic vesicles (27,28). Although the direct binding of fatty acids is controversial (23,29), recent studies indicate a strong potential for an important ...

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Section: Discussionsupporting

confidence: 90%

Section: Mouse Surgery and Tracer Infusionmentioning

confidence: 99%

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Acyl-CoA Synthetase Activity Links Wild-Type but Not Mutant α-Synuclein to Brain Arachidonate Metabolism

et al. 2006

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“…This phenotype may be the result of elevated phospholipase D (PLD) activity because PLD is involved in promoting a reactive state in microglia [4;11;32;40;44] and because Snca tonically inhibits PLD activity in vitro [1;23;37]. We have demonstrated an increase in palmitic acid (16:0) turnover in brain phosphatidylcholine pools in Snca -/-mice [14], consistent with an increase in turnover due to the absence of PLD inhibition by Snca. The increase in TNFα secretion in cultured Snca -/-microglia [3] may result in increased astrocyte PG formation because TNFα increases astrocyte 20:4n-6 release and downstream PG formation [51].…”

Section: Introductionmentioning

confidence: 99%

Brain prostaglandin formation is increased by α-synuclein gene-ablation during global ischemia

Golovko

Murphy

2008

Neuroscience Letters

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We have previously demonstrated that α-synuclein (Snca) gene ablation reduces brain arachidonic acid (20:4n-6) turnover rate in phospholipids through modulation of endoplasmic reticulum-localized acyl-CoA synthetase activity. Although 20:4n-6 is a precursor for prostaglandin (PG), Snca effect on PG levels is unknown. In the present study, we examined the effect of Snca ablation on brain PG level at basal conditions and following 30 sec of global ischemia. Brain PG were extracted with methanol, purified on C 18 cartridges, and analyzed by LC-MS/MS. We demonstrate, for the first time, that Snca gene ablation did not affect brain PG mass under normal physiological conditions. However, total PG mass and masses of individual PG were elevated ∼2-fold upon global ischemia in the absence of Snca. These data are consistent with our previously observed reduction in 20:4n-6 recycling through endoplasmic reticulum-localized acyl-CoA synthetase in the absence of Snca, which may result in the increased 20:4n-6 availability for PG production in the absence of Snca during global ischemia and suggest a role for Snca in brain inflammatory response.

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“…It is found in presynaptic terminals of neurons (Maroteaux et al, 1988;McLean et al, 2000), but also in other regions of neurons as well as within astrocytes and oligodendroglia (Richter-Landsberg et al, 2000;Mori et al, 2002). ␣-Synuclein binds a variety of proteins (Jenco et al, 1998;Peng et al, 2005) and lipid vesicles , and is involved in lipid metabolism (Cabin et al, 2002;Castagnet et al, 2005;Golovko et al, 2005Golovko et al, , 2006. Absence of ␣-synuclein expression is associated with striatal dysfunction (Abeliovich et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

α-Synuclein Expression Modulates Microglial Activation Phenotype

Austin¹,

Floden²,

Murphy³

et al. 2006

J. Neurosci.

131

109

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Recent Parkinson's disease research has focused on understanding the function of the cytosolic protein, ␣-synuclein, and its contribution to disease mechanisms. Within neurons, ␣-synuclein is hypothesized to have a role in regulating synaptic plasticity, vesicle release, and trafficking. In contrast, glial-expressed ␣-synuclein remains poorly described. Here, we examine the consequence of a loss of ␣-synuclein expression on microglial activation. Using a postnatal brain-derived culture system, we defined the phenotype of microglia from wildtype and knock-out ␣-synuclein mice (Scna Ϫ/Ϫ ). Scna Ϫ / Ϫ microglia displayed a basally increased reactive phenotype compared with the wild-type cells and an exacerbated reactive phenotype after stimulation. They also exhibited dramatic morphologic differences compared with wild-type, presenting as large, ramified cells filled with vacuole-like structures. This corresponded with increased protein levels of activation markers, CD68 and ␤1 integrin, in the Scna Ϫ / Ϫ cells. More importantly, Scna Ϫ / Ϫ microglia, after stimulation, secreted elevated levels of proinflammatory cytokines, TNF␣ (tumor necrosis factor ␣) and IL-6 (interleukin-6), compared with wild type. However, despite the reactive phenotype, Scna Ϫ / Ϫ cells had impaired phagocytic ability. We demonstrate for the first time that ␣-synuclein plays a critical role in modulating microglial activation state. We suggest that altered microglial ␣-synuclein expression will affect their phenotype as has already been demonstrated in neurons. This has direct ramifications for the contribution of microglia to the pathophysiology of disease, particularly in familial cases linked to altered ␣-synuclein expression.

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α-Synuclein Gene Deletion Decreases Brain Palmitate Uptake and Alters the Palmitate Metabolism in the Absence of α-Synuclein Palmitate Binding

Cited by 101 publications

References 76 publications

Acyl-CoA Synthetase Activity Links Wild-Type but Not Mutant α-Synuclein to Brain Arachidonate Metabolism

Acyl-CoA Synthetase Activity Links Wild-Type but Not Mutant α-Synuclein to Brain Arachidonate Metabolism

Brain prostaglandin formation is increased by α-synuclein gene-ablation during global ischemia

α-Synuclein Expression Modulates Microglial Activation Phenotype

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