The lipid peroxidation products 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote the formation of α-synuclein oligomers with distinct biochemical, morphological, and functional properties

Näsström, Thomas; Fagerqvist, Therese; Barbu, Mikael; Karlsson, Mikael; Nikolajeff, Fredrik; Kasrayan, Alex; Ekberg, Monica; Lannfelt, Lars; Ingelsson, Martin; Bergström, Joakim

doi:10.1016/j.freeradbiomed.2010.11.027

Cited by 124 publications

(141 citation statements)

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“…Growing evidence suggests that soluble oligomeric forms of α-syn, which precede amyloid formation, are causative triggers for the dopaminergic cell loss occurring in PD [4,5]. The morphology and associated mode of toxicity displayed by alternative types of α-syn oligomers are largely dependent on the environmental conditions under which they have been prepared [6][7][8][9][10][11]. Numerous in vitro and in vivo studies on α-syn oligomers have demonstrated that a toxic gain-offunction occurs in the disease state via two main mechanisms: (i) Ca 2 + imbalances caused by the formation of pore-like complexes within lipid membranes, and (ii) transmembrane seeding that then results in intracellular aggregation [1].…”

Section: Introductionmentioning

confidence: 99%

Distinct higher-order α-synuclein oligomers induce intracellular aggregation

Illes‐Toth

Ramos

Cappai

et al. 2015

Biochemical Journal

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Misfolding and aggregation of α-synuclein (α-syn) into Lewy bodies is associated with a range of neurological disorders, including Parkinson's disease (PD). The cell-to-cell transmission of α-syn pathology has been linked to soluble amyloid oligomer populations that precede Lewy body formation. Oligomers produced in vitro under certain conditions have been demonstrated to induce intracellular aggregation in cell culture models. In the present study, we characterize, by ESI-ion mobility spectrometry (IMS)-MS, a specific population of α-syn oligomers. These MS-compatible oligomers were compared with oligomers with known seeding and pore-forming capabilities and were shown to have the ability to induce intracellular aggregation. Each oligomer type was shown to have distinct epitope profiles that correlated with their toxic gain-of-function. Structurally, the MS compatible oligomers populated a range of species from dimers through to hexamers. Lower-order oligomers were structurally diverse and consistent with unstructured assemblies. Higher-order oligomers were shown to be compact with ring-like structures. The observation of this compact state may explain how this natively disordered protein is able to transfer pathology from cell to cell and avoid degradation by cellular proteases.

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Section: Introductionmentioning

confidence: 99%

Distinct higher-order α-synuclein oligomers induce intracellular aggregation

Illes‐Toth

Ramos

Cappai

et al. 2015

Biochemical Journal

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“…SAXS measurements of dopamine-induced oligomers indicated a globular species with a radius of gyration between 6.7 and 10.5 nm [62]. For HNE-induced αS oligomers, AFM measurements showed protofibril shaped oligomers of 2-4 nm in height and lengths between 100-200 nm [63]. Additionally, annular structures were observed having inner diameters of 30-50 nm, outer diameters of 80-100 nm, and heights of 1-2 nm.…”

Section: Morphologymentioning

confidence: 97%

“…The currently available protocols differ in terms of protein concentration, incubation times, agitation speeds, temperature, and buffer conditions [53][54][55][56][57]. Furthermore, the addition of specific compounds, such as dopamine [58][59][60][61][62], 4-hydroxy-2-nonenal (HNE) [63], docosahexaenoic acid (DHA) [64], lipids [52,[65][66][67][68], organic solvents [56,69], or metal ions [56,57,70] can influence the aggregation of αS resulting in possibly different oligomers.…”

Section: However It Remains An Open Question What the Biologically Mmentioning

confidence: 99%

“…In addition to these preparation protocols without any additional compounds present during aggregation, it has been shown that the morphology of αS oligomers is affected by molecular crowding [82] or by the addition of lipids [52,[65][66][67][68], or organic solvents [56,69], or metal ions [56,57,70]. Furthermore, it has been shown that the aggregation of αS can be influenced by the addition of docosahexaenoic acid (DHA) 13 [64], dopamine [58][59][60][61][62], 4-hydroxy-2-nonenal (HNE) [63], or by using a C-terminally truncated variant αS [83].…”

Section: Morphologymentioning

confidence: 99%

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Parkinson's disease in the spotlight : unraveling nanoscale alpha-synuclein oligomers using ultrasensitive single-molecule spectroscopy

Zijlstra¹

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Niels ZijlstraParkinson's disease in the spotlight Protein folding is an extraordinarily complex process of which the details are still unclear, but is thought to be governed by the energy landscape of the protein and involves a stochastic sampling of many different folds, or conformations, until the protein reaches its thermodynamically most favorable fold [7]. This fold is usually called the native structure of the protein and is mainly determined by the amino acid sequence of the protein [8,9], although the complex environment found in a cell is thought to influence the folding as well [10].The folding of a protein is in some cases co-translational, that is, the folding takes place during synthesis [7,11,12]. In other cases, however, the protein folds in the cytoplasm after a complete synthesis, or is first transported to specific parts of the cell, such as mitochondria or the endoplasmic reticulum, before it folds, see figure 1.1 [7,12].Given the complexity of protein folding and the enormous number of folding events in a cell, it is not surprising that sometimes a protein does not fold correctly or that a protein does not stay folded correctly [1,13]. The protein can get trapped in a local energy minimum resulting in the protein to misfold making the protein toxic [1,14].The more complex the protein folding pathway is, the more likely it is that the folding goes wrong. Normally, a cell can minimize the amount of misfolded proteins by using specialized molecular chaperones or folding catalysts to assist in the folding [4,13]. If the folding still goes wrong, the cell can get rid of the misfolded proteins by degrading them via the ubiquitin-proteasome system, see figure 1.1 [15]. Unfortunately, this defense mechanism does not always work properly. 6 1 1.2. Amyloid diseases and the oligomeric species Amyloid diseases and the oligomeric speciesProtein misfolding and the subsequent aggregation is considered to play an important role in many human neurodegenerative diseases, such as Parkinson's, Alzheimer's, and Huntington's disease, type II diabetes, and in the prion diseases [16]. These diseases are associated with the formation of inter-and intracellular inclusions that mainly contain insoluble amyloid fibrillar aggregates. Amyloid refers to the aggregates having a characteristic cross-β sheet secondary structure. These fibrils are ∼10 nm 7 1 1.2. Amyloid diseases and the oligomeric species in diameter, and can be several microns in length, and thus are composed of many thousands of the constituent monomeric proteins [17]. A commonly used method to detect the formation of amyloid aggregates uses the fluorescent dye Thioflavin T (ThioT). When ThioT binds to β-sheet-rich domains, the dye displays enhanced fluorescence intensity and a characteristic red shift of its emission spectrum. ThioT fluorescence is often used to monitor the kinetics of amyloid formation, which, in general, follows a sigmoidal growth curve that is characterized by an initial lag phase, followed by an exponential growth until it reaches a ...

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“…In paper III the α-syn oligomers and fibrills were prepared as previously described by (Nässtrom et al 2011). Monomeric α-syn was incubated with an of excess 4-hydroxy-2-nonenal (HNE) in sodium carbonate buffer for 18 h at 37°C, while during fibrillary formation incubation was 4-5 days at 37°C on a shaker.…”

Section: α-Synmentioning

confidence: 99%

Neuron-to-neuron propagation of neurodegenerative proteins; relation to degradative systems

Domert¹

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Every year is getting shorter, never seem to find the time Plans that either come to naught or half a page of scribbled lines Hanging on in quiet desperation is the research wayThe time is gone, the thesis over, thought I'd something more to say The general aim of this thesis was to investigate mechanisms associated with neurotoxic peptide activity by Aβ, tau and α-syn in relation to cellular degradation and transfer with a cell-to-cell transfer model system.We found that intercellular transfer of oligomeric Aβ occurs independently of isoform. However, the amount of transfer correlates with each isoforms ability to resist degradation or cellular clearance. The Aβ1-42 isoform showed particular resistance to clearance, which resulted in higher levels of cell-to-cell transfer of the isoform and lysosomal stress caused by accumulation.As Aβ accumulations can inhibit the proteasomal degradation we investigated how reduced proteasomal degradation affected neuron-like cells. We found increased levels of phosphorylated tau protein, disturbed microtubule stability and impaired neuritic transport after reduced proteasomal activity. These changes was partly linked to c-Jun and ERK 1/2 kinase activity.We could also show that α-syn transferred from cell-to-cell in our model system, with a higher degree of transfer for the larger oligomer and fibrillar species. Similar to Aβ, α-syn mainly colocalized with lysosomes, before and after transfer.Lastly, we have developed our cell-to-cell transfer system into a model suitable for high throughput screening (HTS). The type of cells have been upgraded from SH-SY5Y cells to induced pluripotent stem cells (iPSCs), with a differentiation profile more similar to mature neurons. The next step will be screening a small molecular library for substances with inhibitory effect on cell-to-cell transfer of Aβ peptides.The importance of the degradative systems in maintaining protein homeostasis and prevent toxic accumulations in general is well known. Our findings shows the importance of these systems for neurodegenerative diseases and also highlight the link between degradation and cell-to-cell transfer. To restore or enhance the degradative systems would be an interesting avenue to treat neurodegenerative diseases. Another way would be to inhibit the transfer of misfolded protein aggregates. By using the HTS model we developed, a candidate substance with good inhibitory effect on transfer can hopefully be found. Om det går att stoppa överföringen av skadliga proteinansamlingar mellan nervcellerna, är det förmodligen möjligt att bromsa upp sjukdomsutvecklingen av t.ex. Alzheimers sjukdom. Genom att utveckla vårt cellulära modellsystem och anpassa det till ett högkapacitets-screening format, har vi möjliggjort för att testa tiotusentals substanser för att hitta molekyler vilka kan bromsa eller stoppa den cellulära överföringen av beta-amyloid-ansamlingar.

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The lipid peroxidation products 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote the formation of α-synuclein oligomers with distinct biochemical, morphological, and functional properties

Cited by 124 publications

References 60 publications

Distinct higher-order α-synuclein oligomers induce intracellular aggregation

Distinct higher-order α-synuclein oligomers induce intracellular aggregation

Parkinson's disease in the spotlight : unraveling nanoscale alpha-synuclein oligomers using ultrasensitive single-molecule spectroscopy

Neuron-to-neuron propagation of neurodegenerative proteins; relation to degradative systems

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