Alpha-Synuclein Interactions with Membranes

Pirc, Katja; Ulrih, Nataša Poklar

doi:10.5772/16816

Cited by 3 publications

(7 citation statements)

References 99 publications

(188 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, caution is needed when directly comparing calculated binding affinities from various studies, as for α-synuclein often even minute differences in experimental approach can lead to contradicting results. [7,9] Furthermore, in buffered solution α-synuclein exists as an intrinsically disordered monomer, [10] with its conformational heterogeneity extending into higher oligomeric states. [35] For SPR experiment homogenous sample is a prerequisite for satisfactory measurement.…”

Section: Resultsmentioning

confidence: 99%

“…Mounting evidence links both physiological and pathological role(s) of α-synuclein with its association with biological membranes. [4][5][6][7] While native α-synuclein binds to the surface of synaptic vesicles and mediates synaptic plasticity and neurotransmitter release, [4,5] misfolded oligomeric α-synuclein species could contribute to neurotoxicity by membrane disruption. [6] However, Parkinson's disease pathology may be associated with a loss or impairment of physiological α-synuclein-membrane interaction.…”

Section: Introductionmentioning

confidence: 99%

“…[9,12,13,15] The membrane affinity of α-synuclein is highly influenced by bilayer curvature, charge and phase state, chemical composition of the solution (buffer), and lipid:protein ratio. [7][8][9] α-Synuclein may interact better with highly curved surfaces of small unilamellar vesicles (SUVs), [16][17][18] which resemble the size of synaptic vesicles. [19] Depending on the lipid model system the α-helix adopts extended or horseshoe-like conformation.…”

Section: Introductionmentioning

confidence: 99%

“…[14,23] On the contrary, the α-synuclein binding with zwitterionic lipids is still unclear, with various reports on strong, weak, or absent association. [7] However, in addition to electrostatic interactions, hydrophobic interactions are important in the association of α-synuclein with membranes. [23][24][25][26] We have recently shown that the mechanism of α-synuclein binding to lipid membranes is primarily dependent on the surface charge density of the lipid bilayer and the phase state of the lipids.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Interaction of α-Synuclein with Negatively Charged Lipid Membranes Monitored by Surface Plasmon Resonance

Pirc¹,

Hodnik²,

Ulrih³

et al. 2016

Croat. Chem. Acta

Self Cite

View full text Add to dashboard Cite

Aggregation of presynaptic protein α-synuclein is implicated in the development of Parkinson's disease. Interaction of α-synuclein with lipid membranes appears to be critical for its physiological and pathological roles. Anionic lipids trigger conformational transition of α-synuclein from its natively disordered into an α-helical structure. Here we used surface plasmon resonance (SPR) to determine the affinities of α-synuclein for the small unilamellar vesicles composed of anionic 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (POPS) or 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol (DPPG) and neutral 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipids. α-Synuclein bound in a concentration dependent manner to equimolar mixtures of POPC/POPS and POPC/DPPG vesicles. The affinity of α-synuclein for POPC/POPS was ~3 -fold higher than for POPC/DPPG. These results indicate that headgroup charge is not the only factor contributing to α-synuclein-membrane association.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Interaction of α-Synuclein with Negatively Charged Lipid Membranes Monitored by Surface Plasmon Resonance

Pirc¹,

Hodnik²,

Ulrih³

et al. 2016

Croat. Chem. Acta

Self Cite

View full text Add to dashboard Cite

show abstract

“…4 The exact physiological and pathological roles of α-synuclein remain to be resolved, although they appear to involve protein-lipid interactions. 5,6 α-Synuclein fibrillation is a complex nucleationdependent process, which is initiated with the structural conversion of the unfolded monomer into partially structured conformations. 7 Then, via the propagation of diverse oligomeric intermediates, cross-β-sheet fibrils are finally assembled.…”

Section: Introductionmentioning

confidence: 99%

The effect of tyrosine residues on α-synuclein fibrillation

Pirc

Škarabot

Pogačnik

et al. 2015

ACSi

Self Cite

View full text Add to dashboard Cite

Aggregation of the intrinsically disordered protein α-synuclein into ordered amyloid fibrils is implicated in the pathogenesis of Parkinson's disease. To unravel the role of Tyr residues in α-synuclein fibrillation, we prepared recombinant N-terminal (Y39A) and C-terminal (Y(125,133,136)A) mutants of α-synuclein and examined their fibrillation propensities by thioflavin T and 1-anilinonaphthalene-8-sulfonate (ANS) fluorescent probes, SDS-PAGE and atomic force microscopy. We demonstrate that in contrast to wild-type α-synuclein, both mutants show large, but comparable delays in the fibrillation process and exhibit enhanced hydrophobicity during fibril-like assembly. Both Tyr mutants form fibril-like structures after prolonged incubation periods, which are morphologically distinct from those of the wild-type protein.Our results suggest that the N-terminal and C-terminal Tyr residues of α-synuclein are important primarily for the initiation of the fibrillation process.

show abstract

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

Jakubec

Bariås

Furse

et al. 2019

Preprint

View full text Add to dashboard Cite

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.

show abstract

Alpha-Synuclein Interactions with Membranes

Cited by 3 publications

References 99 publications

Interaction of α-Synuclein with Negatively Charged Lipid Membranes Monitored by Surface Plasmon Resonance

Interaction of α-Synuclein with Negatively Charged Lipid Membranes Monitored by Surface Plasmon Resonance

The effect of tyrosine residues on α-synuclein fibrillation

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

Contact Info

Product

Resources

About