Effects of phosphatidylcholine membrane fluidity on the conformation and aggregation of N-terminally acetylated α-synuclein

O’Leary, Emma I.; Jiang, Zhiping; Strub, Marie‐Paule; Lee, Jennifer C.

doi:10.1074/jbc.ra118.002780

Cited by 74 publications

(94 citation statements)

References 67 publications

(94 reference statements)

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“…This suggests that a tighter and more ordered packing of lipids has a negative impact on the α -Syn bilayer interaction, although the presence of net negative charge is a stronger determinant in the current setup. Our findings are consistent with recent studies reporting that cholesterol has negative effect on α -Syn binding 25 , and with reports finding that bilayer fluidity is an important driver for binding alongside charge 4,42 .…”

Section: Introductionsupporting

confidence: 93%

“…Other reports on the effect of cholesterol on α -Syn fibrillation are conflicting. Some studies using lipid vesicles did not observe any promotion of α -Syn fibrillation by lipid vesicles containing cholesterol 25,62 , while other studies observed increased oligomerization in the presence of oxidized cholesterol metabolites 66 or increased fibrillation and deposit formation in cell cultures exposed to higher cholesterol concentrations 67 . The lipid nanodiscs used in our experiments are much smaller (see Table S1) than vesicles used in previous experiments and there is a lack of stored curvature elastic stress.…”

Section: Introductionmentioning

confidence: 94%

“…It has been reported that there is a cholesterol binding site in the Non-Amyloid-Component (NAC) of α -Syn and that cholesterol is essential for the formation of 'amyloid pores' [22][23][24] , which is relatable to the toxic effects that has been proposed for α -Syn oligomers. However, recent work has shown that the presence of cholesterol inhibits the binding of α -Syn to membranes comprising either zwitterionic or anionic lipids 25,26 . The apparent discrepancy in affinity between α -Syn and cholesterol, and the interaction of α -Syn and lipid head groups has, to our knowledge, not been explained adequately.…”

Section: Introductionmentioning

confidence: 99%

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Cholesterol is a strong promotor of an α-Synuclein membrane binding mode that accelerates oligomerization

Jakubec

Bariås

Furse

et al. 2019

Preprint

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Dysregulation of the biosynthesis of cholesterol and other lipids has been implicated in neurological diseases, including Parkinson's disease, where the misfolding of membraneassociated α-Synuclein is a key molecular event. Recent research also suggests that α-Synuclein aggregation is influenced by the lipid environment. The exact molecular mechanisms responsible for cholesterol’s effect on α-Synuclein binding to lipids and how this binding may affect α-Synuclein oligomerization and fibrillation remain elusive, as does the relative importance of cholesterol versus other lipid factors. We probed the interactions and fibrillation behaviour of α-Synuclein using SMA nanodiscs, containing zwitterionic and anionic lipid model systems with and without cholesterol. SPR and ThT fluorescence assays were then employed to monitor α-Synuclein binding, as well as fibrillation in the absence and presence of membrane models. 1H-15N correlated NMR was used to monitor the fold of α-Synuclein in response to nanodisc binding, and we determined individual residue apparent affinities for the nanodisc-contained bilayers. Cholesterol inhibited α-Synuclein interaction with lipid bilayers. We also find that cholesterol significantly promotes α-Synuclein fibrillation, with a more than 20-fold reduction of lag-times before fibrillation onset. When α-Synuclein-bilayer interactions were analysed for individual residues by solution-state NMR, we observed two different effects of cholesterol. In nanodiscs made of DOPC, cholesterol modulated the NAC part of α-Synuclein, leading to stronger interaction of this region with the lipid bilayer. In contrast, in the nanodiscs comprising DOPC, DOPE and DOPG, the NAC part was mostly unaffected by cholesterol, while the binding of the N-terminal and the C-terminal were both inhibited.

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Section: Introductionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cholesterol is a strong promotor of an α-Synuclein membrane binding mode that accelerates oligomerization

Jakubec

Bariås

Furse

et al. 2019

Preprint

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“…cates that Lti30 indeed cross-links the membrane. N-terminally acetylated ␣-synuclein was found to have shortened aggregation kinetics and promoted fibril formation with gel-phase vesicles as compared with fluid membranes (37). Here, we find that Lti30 gives a ThT signal mainly at low pH with fluid membranes, indicative of fibril formation.…”

Section: Modulation Of Membrane Fluidity By Lti30mentioning

confidence: 58%

“…␣-synuclein and CTP:phosphocholine cytidylyltransferase (CCT), that are able to sense lipid-packing defects that are normally enriched in curved surfaces (37,38). Like the dehydrins, the disordered ␣-synuclein and CCT employ induced amphipathic helices that recognize the physical properties of the target membrane surfaces.…”

Section: Modulation Of Membrane Fluidity By Lti30mentioning

confidence: 99%

The disordered plant dehydrin Lti30 protects the membrane during water-related stress by cross-linking lipids

Gupta

Marzinek

Jefferies

et al. 2019

Journal of Biological Chemistry

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Edited by Karen G. Fleming Dehydrins are intrinsically disordered proteins, generally expressed in plants as a response to embryogenesis and waterrelated stress. Their suggested functions are in membrane stabilization and cell protection. All dehydrins contain at least one copy of the highly conserved K-segment, proposed to be a membrane-binding motif. The dehydrin Lti30 (Arabidopsis thaliana) is up-regulated during cold and drought stress conditions and comprises six K-segments, each with two adjacent histidines. Lti30 interacts with the membrane electrostatically via pH-dependent protonation of the histidines. In this work, we seek a molecular understanding of the membrane interaction mechanism of Lti30 by determining the diffusion and molecular organization of Lti30 on model membrane systems by imaging total internal reflection-fluorescence correlation spectroscopy (ITIR-FCS) and molecular dynamics (MD) simulations. The dependence of the diffusion coefficient explored by ITIR-FCS together with MD simulations yields insights into Lti30 binding, domain partitioning, and aggregation. The effect of Lti30 on membrane lipid diffusion was studied on fluorescently labeled supported lipid bilayers of different lipid compositions at mechanistically important pH conditions. In parallel, we compared the mode of diffusion for short individual K-segment peptides. The results indicate that Lti30 binds the lipid bilayer via electrostatics, which restricts the mobility of lipids and bound protein molecules. At low pH, Lti30 binding induced lipid microdomain formation as well as protein aggregation, which could be correlated with one another. Moreover, at physiological pH, Lti30 forms nanoscale aggregates when proximal to the membrane suggesting that Lti30 may protect the cell by "cross-linking" the membrane lipids.Dehydrins are intrinsically disordered stress-related plant proteins that are up-regulated in cold and drought conditions

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A Stearoyl–Coenzyme A Desaturase Inhibitor Prevents Multiple Parkinson Disease Phenotypes in α‐Synuclein Mice

Nuber

Nam

Rajsombath

et al. 2020

Annals of Neurology

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Objective Parkinson disease (PD) has useful symptomatic treatments that do not slow the neurodegenerative process, and no significant disease‐modifying treatments are approved. A key therapeutic target in PD is α‐synuclein (αS), which is both genetically implicated and accumulates in Lewy bodies rich in vesicles and other lipid membranes. Reestablishing αS homeostasis is a central goal in PD. Based on previous lipidomic analyses, we conducted a mouse trial of a stearoyl–coenzyme A desaturase (SCD) inhibitor (“5b”) that prevented αS‐positive vesicular inclusions and cytotoxicity in cultured human neurons. Methods Oral dosing and brain activity of 5b were established in nontransgenic mice. 5b in drinking water was given to mice expressing wild‐type human αS (WT) or an amplified familial PD αS mutation (E35K + E46K + E61K ["3K"]) beginning near the onset of nigral and cortical neurodegeneration and the robust PD‐like motor syndrome in 3K. Motor phenotypes, brain cytopathology, and SCD‐related lipid changes were quantified in 5b‐ versus placebo‐treated mice. Outcomes were compared to effects of crossing 3K to SCD1−/− mice. Results 5b treatment reduced αS hyperphosphorylation in E46K‐expressing human neurons, in 3K neural cultures, and in both WT and 3K αS mice. 5b prevented subtle gait deficits in WT αS mice and the PD‐like resting tremor and progressive motor decline of 3K αS mice. 5b also increased αS tetramers and reduced proteinase K‐resistant lipid‐rich aggregates. Similar benefits accrued from genetically deleting 1 SCD allele, providing target validation. Interpretation Prolonged reduction of brain SCD activity prevented PD‐like neuropathology in multiple PD models. Thus, an orally available SCD inhibitor potently ameliorates PD phenotypes, positioning this approach to treat human α‐synucleinopathies. ANN NEUROL 2021;89:74–90

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Effects of phosphatidylcholine membrane fluidity on the conformation and aggregation of N-terminally acetylated α-synuclein

Cited by 74 publications

References 67 publications

Cholesterol is a strong promotor of an α-Synuclein membrane binding mode that accelerates oligomerization

Cholesterol is a strong promotor of an α-Synuclein membrane binding mode that accelerates oligomerization

The disordered plant dehydrin Lti30 protects the membrane during water-related stress by cross-linking lipids

A Stearoyl–Coenzyme A Desaturase Inhibitor Prevents Multiple Parkinson Disease Phenotypes in α‐Synuclein Mice

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