The Synuclein Family

Lavedan, Christian

doi:10.1101/gr.8.9.871

Cited by 305 publications

(255 citation statements)

References 57 publications

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“…Synucleins are a family of recently identified proteins that share a high level of sequence homology with one another and across species (Lavedan, 1998;Biere et al, 2000). Four members of the synuclein family are known at present: ␣-synuclein, ␤-synuclein, ␥-synuclein, and synorectin (Maroteaux and Scheller, 1988;Surguchov et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Alpha-synuclein deficiency and efferent nerve degeneration in the mouse cochlea: A possible cause of early-onset presbycusis

Park

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Choung

et al. 2011

Neuroscience Research

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Section: Introductionmentioning

confidence: 99%

Alpha-synuclein deficiency and efferent nerve degeneration in the mouse cochlea: A possible cause of early-onset presbycusis

Park

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Choung

et al. 2011

Neuroscience Research

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“…18 b-Synuclein is an abundant synaptic protein originally identified as PNP14 in the bovine brain. 19,20 The most significant difference between the synucleins is that b-synuclein lacks the majority of the hydrophobic nonamyloid component (NAC) domain. 21 This highly amyloidogenic region is responsible for the self-aggregating capacity of a-synuclein.…”

Section: Introductionmentioning

confidence: 99%

An antiaggregation gene therapy strategy for Lewy body disease utilizing β-synuclein lentivirus in a transgenic model

et al. 2004

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Current experimental gene therapy approaches for Parkinson's disease (PD) and dementia with Lewy bodies (DLB) include the use of viral vectors expressing antiapoptosis genes, neurotrophic factors and dopaminergic system enzymes. However, since increasing evidence favors a role for a-synuclein accumulation in the pathogenesis of these disorders, an alternative therapy might require the transfer of genes that might block a-synuclein accumulation. b-Synuclein, the nonamyloidogenic homologue of a-synuclein, has recently been identified as a potential candidate. Thus, in vivo transfer of genes encoding b-synuclein might provide a novel approach to the development of experimental treatments for PD and DLB. To assess this possibility and to better understand the mechanisms involved, a lentiviral vector expressing human (h) b-synuclein (lenti-b-synuclein) was tested in a transgenic (tg) mouse model of ha-synuclein aggregation. This study showed that unilateral intracerebral injection of lenti-b-synuclein reduced the formation of hasynuclein inclusions and the accumulation of ha-synuclein in synapses and ameliorated the neurodegenerative alterations in the tg mice. Both in vivo and in vitro coimmunoprecipitation and immunoblot experiments show that the mechanisms of b-synuclein neuroprotection involve binding of this molecule to ha-synuclein and Akt, resulting in the decreased aggregation and accumulation of ha-synuclein in the synaptic membrane. Together, these data further support a role for b-synuclein in regulating the conformational state of a-synuclein and suggest that this gene transfer approach might have potential for the development of alternative therapies for PD and DLB.

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“…To address the potential role for α-synuclein in brain 20:4n-6 uptake and metabolism, we used steady-state kinetic modeling of [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]20:4n-6 metabolism in vivo coupled with studies using enzyme assays and mRNA expression of key fatty acid metabolic enzymes. These data show, for the first time, a mechanistic explanation for the impact of α-synuclein deficiency on brain lipid metabolism.…”

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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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The Synuclein Family

Cited by 305 publications

References 57 publications

Alpha-synuclein deficiency and efferent nerve degeneration in the mouse cochlea: A possible cause of early-onset presbycusis

Alpha-synuclein deficiency and efferent nerve degeneration in the mouse cochlea: A possible cause of early-onset presbycusis

An antiaggregation gene therapy strategy for Lewy body disease utilizing β-synuclein lentivirus in a transgenic model

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

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