Biophysics of α-synuclein membrane interactions

Pfefferkorn, Candace M.; Jiang, Zhiping; Lee, Jennifer C.

doi:10.1016/j.bbamem.2011.07.032

Cited by 179 publications

(219 citation statements)

References 166 publications

(217 reference statements)

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“…The high affinity of α-synuclein for anionic lipids has been reconciled with the polarized nature of the protein. 50 The N-terminal half is positively charged (+2 at pH 7 and +4 at pH 5.5), and the C-terminal half is negatively charged (−11 at both pH values). A series of repeats in the Nterminal half are arranged so that, if this part folds into an α-helix upon membrane association, the helix has one polar ( Figure 9B) and one hydrophobic ( Figure 9C) side with lysine residues flanking the borders between them.…”

Section: ■ Discussionmentioning

confidence: 99%

“…It has been suggested that the insertion of α-synuclein into the membrane can be facilitated by increasing the available area per phospholipid headgroup in the interface. 50 An increase in lipid headgroup area implies greater exposure of the hydrocarbon region in the bilayer. 51 To investigate this aspect, an additional experiment was conducted using a 7:3 DOPC/DOPS bilayer.…”

Section: Acs Chemical Neurosciencementioning

confidence: 99%

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Adsorption of α-Synuclein to Supported Lipid Bilayers: Positioning and Role of Electrostatics

Hellstrand

Grey

Ainalem

et al. 2013

ACS Chem. Neurosci.

102

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An amyloid form of the protein α-synuclein is the major component of the intraneuronal inclusions called Lewy bodies, which are the neuropathological hallmark of Parkinson's disease (PD). α-Synuclein is known to associate with anionic lipid membranes, and interactions between aggregating α-synuclein and cellular membranes are thought to be important for PD pathology. We have studied the molecular determinants for adsorption of monomeric α-synuclein to planar model lipid membranes composed of zwitterionic phosphatidylcholine alone or in a mixture with anionic phosphatidylserine (relevant for plasma membranes) or anionic cardiolipin (relevant for mitochondrial membranes). We studied the adsorption of the protein to supported bilayers, the position of the protein within and outside the bilayer, and structural changes in the model membranes using two complementary techniquesquartz crystal microbalance with dissipation monitoring, and neutron reflectometry. We found that the interaction and adsorbed conformation depend on membrane charge, protein charge, and electrostatic screening. The results imply that α-synuclein adsorbs in the headgroup region of anionic lipid bilayers with extensions into the bulk but does not penetrate deeply into or across the hydrophobic acyl chain region. The adsorption to anionic bilayers leads to a small perturbation of the acyl chain packing that is independent of anionic headgroup identity. We also explored the effect of changing the area per headgroup in the lipid bilayer by comparing model systems with different degrees of acyl chain saturation. An increase in area per lipid headgroup leads to an increase in the level of α-synuclein adsorption with a reduced water content in the acyl chain layer. In conclusion, the association of α-synuclein to membranes and its adsorbed conformation are of electrostatic origin, combined with van der Waals interactions, but with a very weak correlation to the molecular structure of the anionic lipid headgroup. The perturbation of the acyl chain packing upon monomeric protein adsorption favors association with unsaturated phospholipids preferentially found in the neuronal membrane.

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Section: ■ Discussionmentioning

confidence: 99%

Section: Acs Chemical Neurosciencementioning

confidence: 99%

Adsorption of α-Synuclein to Supported Lipid Bilayers: Positioning and Role of Electrostatics

Hellstrand

Grey

Ainalem

et al. 2013

ACS Chem. Neurosci.

102

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“…aSyn is known to interact with a variety of proteins and small molecules, such as tyrosine hydroxylase and tau, metal ions, and lipids (36 -40). The N-terminal and central NAC domains of aSyn interact with lipids in cellular membranes and with some proteins (41)(42)(43)(44), whereas the C-terminal domain was shown to bind metal ions (38). aSyn interactions with proteins, such as synphilin-1 (45) and tubulin (46), small molecules, and macromolecules, such as dopamine (47), polysaccharides (48), and metal ions (11) can enhance aggregation of aSyn.…”

Section: Discussionmentioning

confidence: 99%

Prolyl Oligopeptidase Enhances α-Synuclein Dimerization via Direct Protein-Protein Interaction

Savolainen

Myöhänen

et al. 2015

Journal of Biological Chemistry

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Background: Prolyl oligopeptidase (PREP) modulates accumulation of aggregated ␣-synuclein both in vitro and in vivo, but the mechanism remains unknown. Results: Using live-cell and cell-free methods, we show that PREP interacts directly with ␣-synuclein. Conclusion: PREP binds to ␣-synuclein and enhances its dimerization. Significance: These results establish a mechanism of how PREP inhibition reduces ␣-synuclein aggregation and support PREP inhibition as a novel therapy in synucleinopathies.

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“…The protein exists in a multitude of conformations that likely dictates the physiological function of α-syn (2-6). Upon membrane association, α-syn adopts an α-helical structure (7), whereas in solution, the protein is disordered (3,6,8). Elucidation of molecular mechanisms underlying the transformation of α-syn to a disease-associated species is still the subject of intense research.…”

Section: Protein-lipid Interactionsmentioning

confidence: 99%

Cysteine cathepsins are essential in lysosomal degradation of α-synuclein

McGlinchey

Lee

2015

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

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188

180

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A cellular feature of Parkinson’s disease is cytosolic accumulation and amyloid formation of α-synuclein (α-syn), implicating a misregulation or impairment of protein degradation pathways involving the proteasome and lysosome. Within lysosomes, cathepsin D (CtsD), an aspartyl protease, is suggested to be the main protease for α-syn clearance; however, the protease alone only generates amyloidogenic C terminal-truncated species (e.g., 1–94, 5–94), implying that other proteases and/or environmental factors are needed to facilitate degradation and to avoid α-syn aggregation in vivo. Using liquid chromatography–mass spectrometry, to our knowledge, we report the first peptide cleavage map of the lysosomal degradation process of α-syn. Studies of purified mouse brain and liver lysosomal extracts and individual human cathepsins demonstrate a direct involvement of cysteine cathepsin B (CtsB) and L (CtsL). Both CtsB and CtsL cleave α-syn within its amyloid region and circumvent fibril formation. For CtsD, only in the presence of anionic phospholipids can this protease cleave throughout the α-syn sequence, suggesting that phospholipids are crucial for its activity. Taken together, an interplay exists between α-syn conformation and cathepsin activity with CtsL as the most efficient under the conditions examined. Notably, we discovered that CtsL efficiently degrades α-syn amyloid fibrils, which by definition are resistant to broad spectrum proteases. This work implicates CtsB and CtsL as essential in α-syn lysosomal degradation, establishing groundwork to explore mechanisms to enhance their cellular activity and levels as a potential strategy for clearance of α-syn.

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Biophysics of α-synuclein membrane interactions

Cited by 179 publications

References 166 publications

Adsorption of α-Synuclein to Supported Lipid Bilayers: Positioning and Role of Electrostatics

Adsorption of α-Synuclein to Supported Lipid Bilayers: Positioning and Role of Electrostatics

Prolyl Oligopeptidase Enhances α-Synuclein Dimerization via Direct Protein-Protein Interaction

Cysteine cathepsins are essential in lysosomal degradation of α-synuclein

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