Characterization of a novel protein regulated during the critical period for song learning in the zebra finch

George, Julia M.; Jin, Hui; Woods, Wendy S.; Clayton, David F.

doi:10.1016/0896-6273(95)90040-3

Cited by 798 publications

(793 citation statements)

References 60 publications

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“…In addition, the Vmax/Km ratio was also significantly depressed in the gene-ablated mice (Table 3), demonstrating that under physiological conditions (75) there would be an effect by α-synuclein on Acsl activity. While we demonstrated the presence of α-synuclen in snca +/+-microsomes (Figure 6), others have also noted that α-synuclein is particularly enriched in microsomal fractions containing primarily ER (23) as well as colocalized with ER in synaptosomal preparations (21,80,89), but not found associated with synaptic vesicles (80).…”

Section: Discussionmentioning

confidence: 50%

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: Discussionmentioning

confidence: 50%

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

et al. 2006

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“…Since then, two groups of diseaseͲcausing mutations have been Predominantly localized to presynaptic nerve terminals, alphaͲsyn can also be found in other neuronal compartments like the cytosol, mitochondriaand nucleus. Although its physiological function is still unknown, it has been proposed to have a role in the integration of presynaptic signaling and neuronal plasticity [155].Prior findings are consistent with these roles, with alphaͲsyn appearing to control synaptic vesicle fusion and recycling. Most data indicate that alphaͲsyn inhibits synaptic transmission in an activityͲdependent manner, as observed in alphaͲsyn deficient mice, exhibiting accelerated recovery of dopaminerelease when presented to multiple stimuli [156].…”

Section: Alphaǧsynuclein (Snca)mentioning

confidence: 83%

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

Perfeito

Cunha‐Oliveira

Rego

2012

Free Radical Biology and Medicine

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“…[8][9][10][11][12] The protein binds lipids and anionic detergents through the seven imperfect, cationic, 11-amino acid repeats located in its N-terminal and hydrophobic regions. [6][7][8][13][14][15][16][17][18][19][20] Electron paramagnetic resonance (EPR) data on its complex with small unilamellar vesicles (SUVs) suggest that the first $100 residues of the monomeric protein adopt an a-helical conformation that lies on the membrane surface. [21][22][23][24][25] The last $40 residues lack defined structure and do not appear to be involved in membrane interactions.…”

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confidence: 99%

¹⁹F NMR studies of α‐synuclein‐membrane interactions

Wang

Pielak

2010

Protein Science

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a-Synuclein function is thought to be related to its membrane binding ability. Solution NMR studies have identified several a-synuclein-membrane interaction modes in small unilamellar vesicles (SUVs), but how membrane properties affect binding remains unclear. Here, we use 19 F NMR to study a-synuclein-membrane interactions by using 3-fluoro-L-tyrosine (3FY) and trifluoromethyl-Lphenylalanine (tfmF) labeled proteins. Our results indicate that the affinity is affected by both the head group and the acyl chain of the SUV. Negatively charged head groups have higher affinity, but different head groups with the same charge also affect binding. We show that the saturation of the acyl chain has a dramatic effect on the a-synuclein-membrane interactions by studying lipids with the same head group but different chains. Taken together, the data show that a-synuclein's N-terminal region is the most important determinate of SUV binding, but its C-terminal region also modulates the interactions. Our data support the existence of multiple tight phospholipid-binding modes, a result incompatible with the model that a-synuclein lies solely on the membrane surface.

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Characterization of a novel protein regulated during the critical period for song learning in the zebra finch

Cited by 798 publications

References 60 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

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

¹⁹F NMR studies of α‐synuclein‐membrane interactions

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Characterization of a novel protein regulated during the critical period for song learning in the zebra finch

Cited by 798 publications

References 60 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

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

19F NMR studies of α‐synuclein‐membrane interactions

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¹⁹F NMR studies of α‐synuclein‐membrane interactions