Exposure to Long Chain Polyunsaturated Fatty Acids Triggers Rapid Multimerization of Synucleins

Perrin, Richard J.; Woods, Wendy S.; Clayton, David F.; George, Julia M.

doi:10.1074/jbc.m105022200

Cited by 254 publications

(253 citation statements)

References 70 publications

(77 reference statements)

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“…38,39 a-Synuclein has several fatty acid binding domains and the association of these with other molecules of a-synuclein promotes aggregation. 38 Thus, it is possible that the binding of b-synuclein to a-synuclein in the cytoplasm might block aggregation by inhibiting translocation of a-synuclein into the plasma membrane and interactions with fatty acids.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Besides studying the structural basis for the putative physiological functions of ␣-synuclein, SDSL could also be used to investigate the conformational changes involved in the transition from unfolded or helical synuclein into toxic oligomeric forms (40). In this respect, it is interesting to note that, at least under some conditions, membrane interaction can facilitate the formation of such oligomers (41)(42)(43) and that modulation of the membrane interaction could be responsible for the formation of toxic oligomers in vivo (44,45). Thus, the molecular understanding of the helical, membrane-bound form discussed here might prove to be an important starting point for our understanding of the misfolding that occurs in disease.…”

Section: Discussionmentioning

confidence: 99%

Structure of membrane-bound α-synuclein studied by site-directed spin labeling

Jao

Der-Sarkissian²,

Chen³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

343

396

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Many of the proposed physiological functions of ␣-synuclein, a protein involved in the pathogenesis of Parkinson's disease, are related to its ability to interact with phospholipids. To better understand the conformational changes that occur upon membrane binding of monomeric ␣-synuclein, we performed EPR analysis of 47 singly labeled ␣-synuclein derivatives. We show that membrane interaction is mediated by major conformational changes within seven N-terminal 11-aa repeats, which reorganize from a highly dynamic structure into an elongated helical structure devoid of significant tertiary packing. Furthermore, we find that analogous positions from different repeats are in equivalent locations with respect to membrane proximity. These and other findings suggest a curved membrane-dependent ␣-helical structure, wherein each 11-aa repeat takes up three helical turns. Similar helical structures could also apply to apolipoproteins and other lipid-interacting proteins with related 11-aa repeats.T he protein ␣-synuclein is the main component of Lewy bodies, a class of intracellular inclusions that is highly characteristic in Parkinson's disease (PD) (1). A causative role of ␣-synuclein in PD has been supported by genetic studies of familial forms of this disease (2-4) as well as by various animal models (5). In addition to its involvement in PD, ␣-synuclein may also play important roles in Alzheimer's disease, dementia with Lewy bodies, multiple system atrophy, and Hallervorden-Spatz syndrome (6, 7).Although not yet fully understood, the physiological function of ␣-synuclein is likely to involve a role in modulating synaptic plasticity (8), presynaptic vesicle pool size, and neurotransmitter release (9-11), as well as vesicle recycling (12). In agreement with these membrane-related functions, ␣-synuclein has been shown to interact with liposomes in vitro (13-16). According to circular dichroism analysis, this interaction causes ␣-synuclein to undergo a conformational change from an unstructured monomer in solution (13,17,18) to an ␣-helical, membrane-bound protein. Based upon sequence analysis, it was recognized early on that the N-terminal portion of ␣-synuclein was likely to mediate lipid interaction (8,13). The N terminus of ␣-synuclein contains seven repeats, each of which is made up of 11 aa (Fig. 1). These repeats are similar to those found in apolipoproteins, and it was proposed that the lipid interaction of ␣-synuclein could be similar to that of the apolipoproteins (8, 13). The involvement of the N terminus in membrane interaction was subsequently confirmed experimentally by analysis of ␣-synuclein deletion mutants (15) and NMR studies of liposomebound ␣-synuclein (18-20). The latter studies revealed an ordering of the N-terminal repeat regions induced upon membrane binding whereas the highly charged C terminus remained unstructured and, therefore, was not involved in membrane interaction. Beyond these data, however, direct structural information, such as the precise location, length, orientation, and number of...

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“…2 h). The decrease in the lag time was attributed to the accelerating role of lipid membrane for fibril formation of the amyloid peptide which has been well established [41].…”

Section: The Inhibition Of Amyloid Formation At Membranementioning

confidence: 99%

A hIAPP‐derived all‐d‐amino‐acid inhibits hIAPP fibrillation efficiently at membrane surface by targeting α‐helical oligomeric intermediates

Wang

Lei

et al. 2014

FEBS Letters

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Edited by Sandro Sonnino ) is demonstrated to inhibit hIAPP fibril formation efficiently both at the phospholipid membrane and in bulk solution. The inhibitor terminates hIAPP aggregation to the a-helical oligomeric intermediates at the membrane surface, whereas it stops the aggregation at the stage of b-sheet oligomeric intermediates in bulk solution. This is the first evidence that the inhibition mechanism of the inhibitor at membrane surface is significantly different from that in bulk solution. Structured summary of protein interactions:hIAPP and hIAPP bind by transmission electron microscopy (View interaction) hIAPP and hIAPP bind by atomic force microscopy (View interaction) hIAPP and hIAPP bind by fluorescence technology (View interaction) hIAPP and hIAPP bind by dynamic light scattering (View interaction)

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Exposure to Long Chain Polyunsaturated Fatty Acids Triggers Rapid Multimerization of Synucleins

Cited by 254 publications

References 70 publications

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

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

Structure of membrane-bound α-synuclein studied by site-directed spin labeling

A hIAPP‐derived all‐d‐amino‐acid inhibits hIAPP fibrillation efficiently at membrane surface by targeting α‐helical oligomeric intermediates

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