The precursor protein of non-Aβ component of Alzheimer's disease amyloid is a presynaptic protein of the central nervous system

Iwai, Akihiko; Masliah, Eliezer; Yoshimoto, Makoto; Ge, Nianfeng; Flanagan, Lisa A.; Silva, H.A Rohan de; Kittel, Ágnes; Saitoh, Tsunao

doi:10.1016/0896-6273(95)90302-x

Cited by 1,265 publications

(1,019 citation statements)

References 38 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%

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%

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

et al. 2006

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“…Double immunocytochemical studies (Figure 3a-d) confirmed these observations and showed that compared to vector controls (Figure 3c), transduced neurons expressing high levels of lenti-b-synuclein displayed reduced accumulation of ha-synuclein ( Figure 3d). In neurons of the treated mice where both synucleins were coexpressed, hasynuclein was identified as discrete, granular aggregates Under physiological conditions a-synuclein is localized primarily to the presynaptic boutons 28 and in LBD and in the tg mice, increased accumulation of hasynuclein in the synapses is associated with functional deficits and synapse loss. 21 To ascertain the effects of lenti-b-synuclein treatment on ha-synuclein accumulation in the nerve terminals, double immunolabeling studies with antibodies against the presynaptic terminal marker synaptophysin and ha-synuclein were performed.…”

Section: Introductionmentioning

confidence: 98%

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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“…1,2 The physiological function of α−Syn remains debatable, but it is thought to play a role in the maintenance of the synaptic vesicle reserve pool of the brain, 3,4 and to possess chaperone-like activity for the assembly of SNARE complexes. 5 α−Syn is remarkable for its structural variety; in aqueous solutions monomeric α−Syn is reported to be a natively unfolded polypeptide chain, although a recent report from Bartels and co-workers suggest that the physiological conformation is an α-helical folded tetramer.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of Membrane Interaction and Disruption by α-Synuclein

et al. 2011

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Parkinson's disease is a common progressive neurodegenerative condition, characterized by the deposition of amyloid fibrils as Lewy bodies in the substantia nigra of affected individuals. These insoluble aggregates predominantly consist of the protein -synuclein. There is increasing evidence suggesting that the aggregation of -synuclein is influenced by lipid membranes and, vice versa, the membrane integrity is severely affected by the presence of bound aggregates. Here, using the surface-sensitive imaging technique supercritical angle fluorescence microscopy and Förster resonance energy transfer, we report the direct observation of -synuclein aggregation on supported lipid bilayers. Both the wild-type and the two mutant forms of -synuclein studied, namely, the familiar variant A53T and the designed highly toxic variant E57K, were found to follow the same mechanism of polymerization and membrane damage. This mechanism involved the extraction of lipids from the bilayer and their clustering around growing -synuclein aggregates. Despite all three isoforms following the same pathway, the extent of aggregation and their effect on the bilayers was seen to be variant and concentration dependent. Both A53T and E57K formed cross--sheet aggregates and damaged the membrane at submicromolar concentrations. The wild-type also formed aggregates in this range; however, the extent of membrane disruption was greatly reduced. The process of membrane damage could resemble part of the yet poorly understood cellular toxicity phenomenon in vivo. AbstractParkinson`s disease is a common progressive neurodegenerative condition, characterized by the deposition of amyloid fibrils as Lewy bodies in the substantia nigra of affected individuals. These insoluble aggregates predominantly consist of the protein α-Synuclein. There is increasing evidence suggesting that the aggregation of α−Synuclein is influenced by lipid membranes and, vice versa, the membrane integrity is severely affected by the presence of bound aggregates. Here, using the surface sensitive imaging technique super critical angle fluorescence microscopy and Förster resonance energy transfer we report the direct observation of α−Synuclein aggregation on supported lipid bilayers. Both the wild-type and the two mutant forms of α−Synuclein studied, namely the familiar variant A53T and the designed highly toxic variant E57K, were found to follow the same mechanism of polymerization and membrane damage. This mechanism involved the extraction of lipids from the bilayer and their clustering around growing α−Synuclein aggregates. Despite all three isoforms following the same pathway, the extent of aggregation and their effect on the bilayers was seen to be variant and concentration dependent. Both A53T and E57K formed cross β-sheet aggregates and damaged the membrane at sub-micromolar concentrations. The wild-type also formed aggregates in this range; however, the extent of membrane disruption was greatly reduced. The process of membrane damage could resemble the yet poorly...

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The precursor protein of non-Aβ component of Alzheimer's disease amyloid is a presynaptic protein of the central nervous system

Cited by 1,265 publications

References 38 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

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

Mechanism of Membrane Interaction and Disruption by α-Synuclein

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