Amyloidogenic Protein–Membrane Interactions: Mechanistic Insight from Model Systems

Butterfield, Sara M.; Lashuel, Hilal A.

doi:10.1002/anie.200906670

Cited by 543 publications

(590 citation statements)

References 226 publications

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“…In order to stabilize the monomeric form of the peptide and reduce aggregation, SDS-d 25 micelles (SDS ¼ sodium dodecyl sulfate) were employed (39)(40)(41)(42). At this condition, the Aβ monomer adopts an α-helical conformation, which has been observed in solution and in contact with other biological molecules and may contribute to initial aggregation pathways leading to the formation of oligomers that have been proposed as the neurotoxic species in AD (5,(43)(44)(45)(46)(47). Therefore, the investigation of the possible interactions with the Aβ monomer using this model is valuable in evaluating the efficiency of our compounds to target and interact with Aβ species.…”

Section: Resultsmentioning

confidence: 99%

Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity

Choi

Braymer

Nanga

et al. 2010

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

251

419

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The accumulation of metal ions and amyloid-β (Aβ) aggregates found in the brain of patients with Alzheimer's disease (AD) has been suggested to be involved in AD pathogenesis. To investigate metal-Aβ-associated pathways in AD, development of chemical tools to target metal-Aβ species is desired. Only a few efforts, however, have been reported. Here, we report bifunctional small molecules, N-(pyridin-2-ylmethyl)aniline (L2-a) and N 1 ,N 1 -dimethyl-N 4 -(pyridin-2-ylmethyl)benzene-1,4-diamine (L2-b) that can interact with both metal ions and Aβ species, as determined by spectroscopic methods including high-resolution NMR spectroscopy. Using the bifunctional compound L2-b, metal-induced Aβ aggregation and neurotoxicity were modulated in vitro as well as in human neuroblastoma cells. Furthermore, treatment of human AD brain tissue homogenates containing metal ions and Aβ species with L2-b showed disassembly of Aβ aggregates. Therefore, our studies presented herein demonstrate the value of bifunctional compounds as chemical tools for investigating metal-Aβ-associated events and their mechanisms in the development and pathogenesis of AD and as potential therapeutics.amyloid-β peptide | copper | zinc | reactive oxygen species | rational structure-based design M ore than 24 million people worldwide have Alzheimer's disease (AD), a devastating and fatal form of dementia (1-3). The key pathological markers in AD are amyloid-β (Aβ) plaques and neurofibrillary tangles, the accumulation of which is accompanied by oxidative stress, inflammation, and neurodegeneration. The "amyloid hypothesis" in AD states that Aβ, generated via cleavage of the amyloid precursor protein (APP) by β-and γ-secretases, is a proximal causative agent (1-4). It is, however, still unclear which morphological Aβ species, from soluble small oligomers to large fibrils, are central to AD pathogenesis (1-5).In addition to Aβ aggregate deposits, dyshomeostasis and miscompartmentalization of metal ions such as Fe, Cu, and Zn ions clearly occur in AD brains (1-4, 6-10). Some studies suggest that highly concentrated metal ions play an important role in Aβ aggregate deposition and neurotoxicity including the formation of reactive oxygen species (ROS) such as hydrogen peroxide (H 2 O 2 ) (1-4, 6-13). The role of metal ions in AD and molecular mechanisms of metal-Aβ-associated pathological pathways, however, are not fully understood. Using traditional metal chelating agents, potential regulation of metal-induced Aβ aggregation and neurotoxicity has been shown in vitro and in vivo (1-4, 6, 10, 13-17). Some compounds such as clioquinol (CQ) and an 8-hydroxyquinoline derivative (PBT2) have moved into clinical trials and showed improved cognition. Long-term use of CQ is, however, limited by an adverse side effect, subacute myelo-optic neuropathy (18). Although these traditional metal chelators have yet to be available as therapeutic agents, the studies using these compounds show the possible involvement of metal ions in AD pathogenesis.To elucidate the pathological ...

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Section: Resultsmentioning

confidence: 99%

Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity

Choi

Braymer

Nanga

et al. 2010

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

251

419

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“…There is considerable evidence that amyloid assemblies interact with membranes, supporting the notion that these interactions may play a role in amyloid-associated cellular dysfunction (11,13,34). However, the physical basis for these interactions and the mechanisms of amyloid-induced dysfunction remain unresolved.…”

Section: Discussionmentioning

confidence: 99%

“…In some systems, there is evidence suggesting that prefibrillar oligomers, rather than the fully formed fibrils, are the source of toxicity (8,9). In these cases, cytotoxicity is thought to result from the formation of specific membrane pores (10,11) although alternative models including membrane destabilization or membrane thinning have also been proposed (12)(13)(14)(15). In other cases, toxicity may reside with the amyloid fibrils themselves.…”

mentioning

confidence: 99%

Direct three-dimensional visualization of membrane disruption by amyloid fibrils

Milanesi

Sheynis

Xue

et al. 2012

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

167

171

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Protein misfolding and aggregation cause serious degenerative conditions such as Alzheimer's, Parkinson, and prion diseases. Damage to membranes is thought to be one of the mechanisms underlying cellular toxicity of a range of amyloid assemblies. Previous studies have indicated that amyloid fibrils can cause membrane leakage and elicit cellular damage, and these effects are enhanced by fragmentation of the fibrils. Here we report direct 3D visualization of membrane damage by specific interactions of a lipid bilayer with amyloid-like fibrils formed in vitro from β 2 -microglobulin (β 2 m). Using cryoelectron tomography, we demonstrate that fragmented β 2 m amyloid fibrils interact strongly with liposomes and cause distortions to the membranes. The normally spherical liposomes form pointed teardrop-like shapes with the fibril ends seen in proximity to the pointed regions on the membranes. Moreover, the tomograms indicated that the fibrils extract lipid from the membranes at these points of distortion by removal or blebbing of the outer membrane leaflet. Tiny (15-25 nm) vesicles, presumably formed from the extracted lipids, were observed to be decorating the fibrils. The findings highlight a potential role of fibrils, and particularly fibril ends, in amyloid pathology, and report a previously undescribed class of lipid-protein interactions in membrane remodelling.T he failure of molecular chaperones to prevent the accumulation of misfolded proteins results in protein aggregation and amyloid formation, processes associated with severe human degenerative diseases (1, 2). Despite the attention focused on these problems during the century since these disorders were first identified (3-5) and advances in understanding the structure of the cross-β conformation of amyloid fibrils in atomic detail (6, 7), the basic pathological mechanisms of amyloidosis remain poorly understood and therapeutic intervention is lacking. The identity of the toxic species and the mechanisms of cytotoxicity remain major unsolved problems. In some systems, there is evidence suggesting that prefibrillar oligomers, rather than the fully formed fibrils, are the source of toxicity (8, 9). In these cases, cytotoxicity is thought to result from the formation of specific membrane pores (10, 11) although alternative models including membrane destabilization or membrane thinning have also been proposed (12-15). In other cases, toxicity may reside with the amyloid fibrils themselves. Evidence that toxicity correlates with fibrillar assemblies has been reported for yeast and mammalian prion proteins (16, 17), human lysozyme (18), Huntingtin exon 1, α-synuclein (19), and Amyloid-β (Aβ) (20, 21). Furthermore, Aβ plaques have been shown to form rapidly in vivo and to precede neuropathological changes in a mouse model (22). The end surfaces of fibrils (herein termed "fibril ends") are unusually reactive entities: they play a key role in catalyzing recruitment and conformational conversion of amyloid-forming proteins (23, 24) and provide the sites for templated...

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“…During the last decade a growing body of evidence suggested that the toxic species of αS are pre-fibrillar misfolded forms rather than insoluble neuronal deposits as found in Lewy bodies (Caughey and Lansbury, 2003;Cookson, 2009;Karpinar et al, 2009;Lashuel et al, 2002;Winner et al, 2011). One prevalent hypothesis attributes the toxicity of αS oligomers to their high membrane affinity, which might cause membrane distortion and membrane leakage (Auluck, 2010;Bodner et al, 2009;Butterfield and Lashuel, 2010;Karpinar et al, 2009). …”

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confidence: 99%

α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner

Yin¹,

Fonseca²,

Eisbach³

et al. 2014

Neurobiology of Disease

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Alpha-synuclein (αS) misfolding is associated with Parkinson's disease (PD) but little is known about the mechanisms underlying αS toxicity. Increasing evidence suggests that defects in membrane transport play an important role in neuronal dysfunction. Here we demonstrate that the GTPase Rab8a interacts with αS in rodent brain. NMR spectroscopy reveals that the C-terminus of αS binds to the functionally important switch region as well as the C-terminal tail of Rab8a. In line with a direct Rab8a/αS interaction, Rab8a enhanced αS aggregation and reduced αS-induced cellular toxicity. In addition, Rab8 -the Drosophila ortholog of Rab8a -ameliorated αS-oligomer specific locomotor impairment and neuron loss in fruit flies. In support of the pathogenic relevance of the αS-Rab8a interaction, phosphorylation of αS at S129 enhanced binding to Rab8a, increased formation of insoluble αS aggregates and reduced cellular toxicity. Our study provides novel mechanistic insights into the interplay of the GTPase Rab8a and αS cytotoxicity, and underscores the therapeutic potential of targeting this interaction.

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Amyloidogenic Protein–Membrane Interactions: Mechanistic Insight from Model Systems

Abstract: Reviews 5628 www.angewandte.org

Cited by 543 publications

References 226 publications

Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity

Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity

Direct three-dimensional visualization of membrane disruption by amyloid fibrils

α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner

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