α-Synuclein aggregation, seeding and inhibition by scyllo-inositol

Ibrahim, Tarek; McLaurin, JoAnne

doi:10.1016/j.bbrc.2015.12.043

Cited by 23 publications

(19 citation statements)

References 22 publications

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“…Electron microscopy was conducted according to published methods [ 56 ]. Briefly, 1 % Pioloform-coated copper grids (Canemco #G300HEX, Canada) were charged using a glow discharge apparatus (Quorum Technologies, Laughton, East Sussex, UK) at 0.15 Torr × 15 s, 5 mA, and 2 μl of 1 μg/μl amyloid-β 1-40 in PBS was loaded for 1 min, wicked to remove large solvent droplets and allowed to air dry.…”

Section: Methodsmentioning

confidence: 99%

Brain omega-3 polyunsaturated fatty acids modulate microglia cell number and morphology in response to intracerebroventricular amyloid-β 1-40 in mice

Hopperton

Trépanier

Giuliano

et al. 2016

J Neuroinflammation

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BackgroundNeuroinflammation is a proposed mechanism by which Alzheimer’s disease (AD) pathology potentiates neuronal death and cognitive decline. Consumption of omega-3 polyunsaturated fatty acids (PUFA) is associated with a decreased risk of AD in human observational studies and exerts protective effects on cognition and pathology in animal models. These fatty acids and molecules derived from them are known to have anti-inflammatory and pro-resolving properties, presenting a potential mechanism for these protective effects.MethodsHere, we explore this mechanism using fat-1 transgenic mice and their wild type littermates weaned onto either a fish oil diet (high in n-3 PUFA) or a safflower oil diet (negligible n-3 PUFA). The fat-1 mouse carries a transgene that enables it to convert omega-6 to omega-3 PUFA. At 12 weeks of age, mice underwent intracerebroventricular (icv) infusion of amyloid-β 1-40. Brains were collected between 1 and 28 days post-icv, and hippocampal microglia, astrocytes, and degenerating neurons were quantified by immunohistochemistry with epifluorescence microscopy, while microglia morphology was assessed with confocal microscopy and skeleton analysis.ResultsFat-1 mice fed with the safflower oil diet and wild type mice fed with the fish oil diet had higher brain DHA in comparison with the wild type mice fed with the safflower oil diet. Relative to the wild type mice fed with the safflower oil diet, fat-1 mice exhibited a lower peak in the number of labelled microglia, wild type mice fed with fish oil had fewer degenerating neurons, and both exhibited alterations in microglia morphology at 10 days post-surgery. There were no differences in astrocyte number at any time point and no differences in the time course of microglia or astrocyte activation following infusion of amyloid-β 1-40.ConclusionsIncreasing brain DHA, through either dietary or transgenic means, decreases some elements of the inflammatory response to amyloid-β in a mouse model of AD. This supports the hypothesis that omega-3 PUFA may be protective against AD by modulating the immune response to amyloid-β.

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Section: Methodsmentioning

confidence: 99%

Brain omega-3 polyunsaturated fatty acids modulate microglia cell number and morphology in response to intracerebroventricular amyloid-β 1-40 in mice

Hopperton

Trépanier

Giuliano

et al. 2016

J Neuroinflammation

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“…There is strong interest in the discovery of small compounds that can act as chemical chaperones modulating the aggregation of α-syn [15,16,17,18,19,20]. In the absence of a defined 3D-structure to target, screening of large collections of chemically diverse compounds is a useful approach toward the discovery of novel bioactive molecules exhibiting an α-syn anti-aggregational effect.…”

Section: Introductionmentioning

confidence: 99%

High-Throughput Screening Methodology to Identify Alpha-Synuclein Aggregation Inhibitors

Pujols

Peña-Díaz

Conde-Giménez

et al. 2017

IJMS

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An increasing number of neurodegenerative diseases are being found to be associated with the abnormal accumulation of aggregated proteins in the brain. In Parkinson’s disease, this process involves the aggregation of alpha-synuclein (α-syn) into intraneuronal inclusions. Thus, compounds that inhibit α-syn aggregation represent a promising therapeutic strategy as disease-modifying agents for neurodegeneration. The formation of α-syn amyloid aggregates can be reproduced in vitro by incubation of the recombinant protein. However, the in vitro aggregation of α-syn is exceedingly slow and highly irreproducible, therefore precluding fast high throughput anti-aggregation drug screening. Here, we present a simple and easy-to-implement in-plate method for screening large chemical libraries in the search for α-syn aggregation modulators. It allows us to monitor aggregation kinetics with high reproducibility, while being faster and requiring lower protein amounts than conventional aggregation assays. We illustrate how the approach enables the identification of strong aggregation inhibitors in a library of more than 14,000 compounds.

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“…Usually, the aromatic rings form a planar hydrophobic core that is thought to interact with apolar exposed regions in α-Syn or its assemblies. However, despite the presence of multiple aromatic groups is recurrent in natural α-Syn aggregation inhibitors and many of the reported screening efforts result in the identification of this kind of molecules, several natural compounds exhibiting a single aromatic ring have been shown to act as α-Syn aggregation modulators ( Supplementary Figure S3), including scyllo-inositol, gallic acid, dopamine, safranal and caffeic acid (Herrera et al, 2008;Di Giovanni et al, 2010;Liu et al, 2014;Ibrahim and McLaurin, 2016;Save et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of α-Synuclein Aggregation and Mature Fibril Disassembling With a Minimalistic Compound, ZPDm

Peña-Díaz

Pujols

Pinheiro

et al. 2020

Front. Bioeng. Biotechnol.

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Synucleinopathies are a group of disorders characterized by the accumulation of α-Synuclein amyloid inclusions in the brain. Preventing α-Synuclein aggregation is challenging because of the disordered nature of the protein and the stochastic nature of fibrillogenesis, but, at the same time, it is a promising approach for therapeutic intervention in these pathologies. A high-throughput screening initiative allowed us to discover ZPDm, the smallest active molecule in a library of more than 14.000 compounds. Although the ZPDm structure is highly related to that of the previously described ZPD-2 aggregation inhibitor, we show here that their mechanisms of action are entirely different. ZPDm inhibits the aggregation of wild-type, A30P, and H50Q α-Synuclein variants in vitro and interferes with α-Synuclein seeded aggregation in protein misfolding cyclic amplification assays. However, ZPDm distinctive feature is its strong potency to dismantle preformed α-Synuclein amyloid fibrils. Studies in a Caenorhabditis elegans model of Parkinson's Disease, prove that these in vitro properties are translated into a significant reduction in the accumulation of α-Synuclein inclusions in ZPDm treated animals. Together with previous data, the present work illustrates how different chemical groups on top of a common molecular scaffold can result in divergent but complementary anti-amyloid activities.

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α-Synuclein aggregation, seeding and inhibition by scyllo-inositol

Cited by 23 publications

References 22 publications

Brain omega-3 polyunsaturated fatty acids modulate microglia cell number and morphology in response to intracerebroventricular amyloid-β 1-40 in mice

Brain omega-3 polyunsaturated fatty acids modulate microglia cell number and morphology in response to intracerebroventricular amyloid-β 1-40 in mice

High-Throughput Screening Methodology to Identify Alpha-Synuclein Aggregation Inhibitors

Inhibition of α-Synuclein Aggregation and Mature Fibril Disassembling With a Minimalistic Compound, ZPDm

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