Distinct Membrane Disruption Pathways Are Induced by 40-Residue β-Amyloid Peptides

Delgado, Dennis A.; Doherty, Katelynne E.; Cheng, Qi; Kim, Hyeongeun; Xu, Dawei; Dong, He; Grewer, Christof; Wang, Qiang

doi:10.1074/jbc.m116.720656

Cited by 52 publications

(75 citation statements)

References 57 publications

(86 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A number of other amyloidogenic polypeptides have been found to undergo lipid-induced aggregation coupled to membrane permeabilization, including islet amyloid polypeptide (IAPP) involved in diabetes [2, 19, 33] and Aβ peptide associated with AD neuropathology [14]. The results presented here imply that protein binding partners could also interfere with the aggregation of these polypeptides at the membrane surface.…”

Section: Discussionmentioning

confidence: 79%

Endosulfine-alpha inhibits membrane-induced α-synuclein aggregation and protects against α-synuclein neurotoxicity

Ysselstein

Dehay

Costantino

et al. 2017

acta neuropathol commun

View full text Add to dashboard Cite

Neuropathological and genetic findings suggest that the presynaptic protein α-synuclein (aSyn) is involved in the pathogenesis of synucleinopathy disorders, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy. Evidence suggests that the self-assembly of aSyn conformers bound to phospholipid membranes in an aggregation-prone state plays a key role in aSyn neurotoxicity. Accordingly, we hypothesized that protein binding partners of lipid-associated aSyn could inhibit the formation of toxic aSyn oligomers at membrane surfaces. To address this hypothesis, we characterized the protein endosulfine-alpha (ENSA), previously shown to interact selectively with membrane-bound aSyn, in terms of its effects on the membrane-induced aggregation and neurotoxicity of two familial aSyn mutants, A30P and G51D. We found that wild-type ENSA, but not the non-aSyn-binding S109E variant, interfered with membrane-induced aSyn self-assembly, aSyn-mediated vesicle disruption and aSyn neurotoxicity. Immunoblotting analyses revealed that ENSA was down-regulated in the brains of synucleinopathy patients versus non-diseased individuals. Collectively, these results suggest that ENSA can alleviate neurotoxic effects of membrane-bound aSyn via an apparent chaperone-like activity at the membrane surface, and a decrease in ENSA expression may contribute to aSyn neuropathology in synucleinopathy disorders. More generally, our findings suggest that promoting interactions between lipid-bound, amyloidogenic proteins and their binding partners is a viable strategy to alleviate cytotoxicity in a range of protein misfolding disorders.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0403-7) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 79%

Endosulfine-alpha inhibits membrane-induced α-synuclein aggregation and protects against α-synuclein neurotoxicity

Ysselstein

Dehay

Costantino

et al. 2017

acta neuropathol commun

View full text Add to dashboard Cite

show abstract

“…The key motif of Aβ peptides induces cellular membrane disruption, which has made it a potential target for pharmacological inventions recently [116–118]. The kinetic and thermodynamic parameters of the dominant pathway of cellular disruption have been studied to be able to enhance pharmacological applications [119]. …”

Section: Peptide-peptide Interaction Driven Self-assemblymentioning

confidence: 99%

Self-assembling peptide-based building blocks in medical applications

Acar

Srivastava

Chung

et al. 2017

Advanced Drug Delivery Reviews

193

155

View full text Add to dashboard Cite

Peptides and peptide-conjugates, comprising natural and synthetic building blocks, are an increasingly popular class of biomaterials. Self-assembled nanostructures based on peptides and peptide-conjugates offer advantages such as precise selectivity and multifunctionality that can address challenges and limitations in the clinic. In this review article, we discuss recent developments in the design and self-assembly of various nanomaterials based on peptides and peptide-conjugates for medical applications, and categorize them into two themes based on the driving forces of molecular self-assembly. First, we present the self-assembled nanostructures driven by the supramolecular interactions between the peptides, with or without the presence of conjugates. The studies where nanoassembly is driven by the interactions between the conjugates of peptide-conjugates are then presented. Particular emphasis is given to in vivo studies focusing on therapeutics, diagnostics, immune modulation and regenerative medicine, and challenges and future perspective are presented.

show abstract

“…One recent single-molecular imaging study utilized sub-μM Aβ concentration and reported formation of small oligomers on membrane surfaces with restricted mobility, which might represent the nucleation step of Aβ in membrane-related environments [29]. A variety of membrane disruption effects have been observed in these model systems, including the leakage of liposome content [23,30], changes in membrane curvatures [31], lipid uptake [32] and vesicle fusion [33,34]. There may be a mixture of several different membrane disruption effects in a particular system.…”

Section: Introductionmentioning

confidence: 99%

“…It has been considered that the formation of ion channel might serve as a common mechanism in different types of amyloid diseases. In addition to the ion channel hypothesis, it has also been reported that large Aβ oligomers had the ability to fragmentize the lipid bilayers through detergent-like mechanisms, where the oligomeric cores were surrounded and stabilized by lipids [30,32]. Recently, it was suggested that the two processes might occur in steps, where the ion channels formed initially, and membrane fragmentation was induced at later stages.…”

Section: Introductionmentioning

confidence: 99%

“…We have recently showed the reduction of systematic heterogeneity using simple model liposomes with only the zwitterionic lipid 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (POPC) and the negatively charged 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphoglycerol (POPG) and 40-residue Aβ (Aβ40) peptides [30]. Our results suggested three distinct membrane disruption effects, namely the leakage of liposome contents, the vesicle fusion and the membrane fragmentation, became predominant in individual model systems with well-controlled conditions.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The on-fibrillation-pathway membrane content leakage and off-fibrillation-pathway lipid mixing induced by 40-residue β-amyloid peptides in biologically relevant model liposomes

Cheng

Doherty

et al. 2018

Biochimica et Biophysica Acta (BBA) - Biomembranes

Self Cite

View full text Add to dashboard Cite

Disruption of the synaptic plasma membrane (SPM) induced by the aggregation of β-amyloid (Aβ) peptides has been considered as a potential mechanism for the neurotoxicity of Aβ in Alzheimer's disease (AD). However, the molecular basis of such membrane disruption process remains unclear, mainly because of the severe systematic heterogeneity problem that prevents the high-resolution studies. Our previous studies using a two-component phosphatidylcholine (PC)/phosphatidylglycerol (PG) model liposome showed the presence of Aβ-induced membrane disruptions that were either on the pathway or off the pathway of fibril formation. The present study focuses on a more biologically relevant model membrane with compositions that mimic the outer leaflet of SPMs. The main findings are: (1) the two competing membrane disruption effects discovered in PC/PG liposomes and their general peptide-to-lipid-molar-ratio dependence persist in the more complicated membrane models; (2) the SPM-mimic membrane promotes the formation of certain "on-fibrillation-pathway" intermediates with higher α-helical structural population, which lead to more rapid and significant of membrane content leakage; (3) although the "on-fibrillation-pathway" intermediate structures show dependence on membrane compositions, there seems to be a common final fibril structure grown from different liposomes, suggesting that there may be a predominant fibril structure for 40-residue Aβ (i.e. Aβ) peptides in biologically-relevant membranes. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy.

show abstract

Distinct Membrane Disruption Pathways Are Induced by 40-Residue β-Amyloid Peptides

Cited by 52 publications

References 57 publications

Endosulfine-alpha inhibits membrane-induced α-synuclein aggregation and protects against α-synuclein neurotoxicity

Endosulfine-alpha inhibits membrane-induced α-synuclein aggregation and protects against α-synuclein neurotoxicity

Self-assembling peptide-based building blocks in medical applications

The on-fibrillation-pathway membrane content leakage and off-fibrillation-pathway lipid mixing induced by 40-residue β-amyloid peptides in biologically relevant model liposomes

Contact Info

Product

Resources

About