Cell and tissue distribution and developmental change of neuron specific 14 kDa protein (phosphoneuroprotein 14)

Shibayama-Imazu, Toshiko; Okahashi, Ikuko; Omata, Kumiko; Nakajo, Shigeo; Ochiai, Hidehiko; Nakai, Yasumitsu; Hama, Tokiko; Nakamura, Yasuharu; Nakaya, Kazuyasu

doi:10.1016/0006-8993(93)90796-p

Cited by 118 publications

(86 citation statements)

References 31 publications

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“…Others have shown that α-synuclein is enriched in microsomes (23) and total brain protein is comprised of between 0.1% to 1.0% α-synuclein (79,80). We confirmed the presence of α-synuclein in our wt brain microsomes using Western blot analysis ( Figure 6).…”

Section: Wt But Not Mutant α-Synuclein Restores Acyl-coa Synthetase Asupporting

confidence: 82%

“…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: 49%

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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: Wt But Not Mutant α-Synuclein Restores Acyl-coa Synthetase Asupporting

confidence: 82%

Section: Discussionmentioning

confidence: 49%

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

et al. 2006

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“…In addition, we have found that this function is greatly altered when ␣-synuclein includes A30P, a mutation associated with autosomal dominant forms of PD. In all our experiments, the concentrations of ␣-synucleins used were analogous to the average levels of the protein in the brain (Shibayama-Imazu et al, 1993;Nakajo et al, 1996) and lower than those existing in at least some synapses (Fortin et al, 2005;Tao-Cheng, 2006). Our results therefore cannot depend on excess of the protein, rather, they demonstrate that the ␣-synuclein/actin interaction can have an important role in both the physiology and the pathology of the brain.…”

Section: Discussionmentioning

confidence: 55%

“…N2A cells express very low levels of endogenous ␣-synuclein, hardly appreciable by either Western blotting or immunocytochemistry (Figure 3, A-D). In these cells, concentrations of ␣-synucleins comparable to those existing in the brain (Shibayama-Imazu et al, 1993;Nakajo et al, 1996) were reached by either delivery of recombinant wt or A30P ␣-synucleins or transfection of the corresponding cDNAs. The concentration of exogenous ␣-synucleins in the cells loaded by SLO permeabilization (Walev et al, 2001) followed by Ca 2ϩ -dependent membrane resealing was ϳ5 M, as revealed by Western blotting (Figure 3A).…”

Section: A30p ␣-Synuclein Induces Cytoskeleton Disruption In N2a Cellsmentioning

confidence: 99%

α-Synuclein and Its A30P Mutant Affect Actin Cytoskeletal Structure and Dynamics

Sousa

Bellani

Giannandrea

et al. 2009

MBoC

107

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The function of ␣-synuclein, a soluble protein abundant in the brain and concentrated at presynaptic terminals, is still undefined. Yet, ␣-synuclein overexpression and the expression of its A30P mutant are associated with familial Parkinson's disease. Working in cell-free conditions, in two cell lines as well as in primary neurons we demonstrate that ␣-synuclein and its A30P mutant have different effects on actin polymerization. Wild-type ␣-synuclein binds actin, slows down its polymerization and accelerates its depolymerization, probably by monomer sequestration; A30P mutant ␣-synuclein increases the rate of actin polymerization and disrupts the cytoskeleton during reassembly of actin filaments. Consequently, in cells expressing mutant ␣-synuclein, cytoskeleton-dependent processes, such as cell migration, are inhibited, while exo-and endocytic traffic is altered. In hippocampal neurons from mice carrying a deletion of the ␣-synuclein gene, electroporation of wild-type ␣-synuclein increases actin instability during remodeling, with growth of lamellipodia-like structures and apparent cell enlargement, whereas A30P ␣-synuclein induces discrete actin-rich foci during cytoskeleton reassembly. In conclusion, ␣-synuclein appears to play a major role in actin cytoskeletal dynamics and various aspects of microfilament function. Actin cytoskeletal disruption induced by the A30P mutant might alter various cellular processes and thereby play a role in the pathogenesis of neurodegeneration.

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“…␣-Synuclein is enriched in presynaptic terminals (9 -11) and is expressed rather ubiquitously in the brain, particularly in the neocortex, hippocampus, striatum, thalamus, and cerebellum (12). Its expression is developmentally regulated, redistributing from neuronal cell bodies to synaptic terminals during periods of neuronal differentiation (13,14). Its expression is up-regulated during periods of synaptic plasticity, i.e.…”

mentioning

confidence: 99%

Effect of Mutant α-Synuclein on Dopamine Homeostasis in a New Human Mesencephalic Cell Line

Lotharius¹,

Barg²,

Wiekop³

et al. 2002

Journal of Biological Chemistry

326

266

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Mutations in ␣-synuclein have been linked to rare, autosomal dominant forms of Parkinson's disease. Despite its ubiquitous expression, mutant ␣-synuclein primarily leads to the loss of dopamine-producing neurons in the substantia nigra. ␣-Synuclein is a presynaptic nerve terminal protein of unknown function, although several studies suggest it is important for synaptic plasticity and maintenance. The present study utilized a new human mesencephalic cell line, MESC2.10, to study the effect of A53T mutant ␣-synuclein on dopamine homeostasis. In addition to expressing markers of mature dopamine neurons, differentiated MESC2.10 cells are electrically active, produce dopamine, and express wildtype human ␣-synuclein. Lentivirus-induced overexpression of A53T mutant ␣-synuclein in differentiated MESC2.10 cells resulted in down-regulation of the vesicular dopamine transporter (VMAT2), decreased potassium-induced and increased amphetamine-induced dopamine release, enhanced cytoplasmic dopamine immunofluorescence, and increased intracellular levels of superoxide. These results suggest that mutant ␣-synuclein leads to an impairment in vesicular dopamine storage and consequent accumulation of dopamine in the cytosol, a pathogenic mechanism that underlies the toxicity of the psychostimulant amphetamine and the parkinsonian neurotoxin 1-methyl-4-phenylpyridinium. Interestingly, cells expressing A53T mutant ␣-synuclein were resistant to amphetamine-induced toxicity. Because extravesicular, cytoplasmic dopamine can be easily oxidized into reactive oxygen species and other toxic metabolites, mutations in ␣-synuclein might lead to Parkinson's disease by triggering protracted, low grade dopamine toxicity resulting in terminal degeneration and ultimately cell death.

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Cell and tissue distribution and developmental change of neuron specific 14 kDa protein (phosphoneuroprotein 14)

Cited by 118 publications

References 31 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

α-Synuclein and Its A30P Mutant Affect Actin Cytoskeletal Structure and Dynamics

Effect of Mutant α-Synuclein on Dopamine Homeostasis in a New Human Mesencephalic Cell Line

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