The hot sites of α-synuclein in amyloid fibril formation

Khammari, Anahita; Arab, Seyed Shahriar; Ejtehadi, Mohammad Reza

doi:10.1038/s41598-020-68887-2

Cited by 11 publications

(6 citation statements)

References 66 publications

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“…The N-terminal aSyn residues 35–43 constitute one of the hotspots controlling aSyn aggregation ( Doherty et al, 2020 ; Khammari et al, 2020 ). They are targeted not only by AS69 but also by some of the aSyn antibodies tested for application in PD patients.…”

Section: Discussionmentioning

confidence: 99%

“…AS69 therefore represents a new paradigm in amyloid inhibition. The aSyn N-terminal region is critical for aSyn aggregation ( Mirecka et al, 2014 ; Shaykhalishahi et al, 2015 ; Doherty et al, 2020 ; Khammari et al, 2020 ). On a biophysical level, AS69 binding interferes with primary and secondary nucleation processes and inhibits the proliferation of aSyn fibrils ( Agerschou et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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A β-Wrapin Targeting the N-Terminus of α-Synuclein Monomers Reduces Fibril-Induced Aggregation in Neurons

et al. 2021

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Reducing α-synuclein pathology constitutes a plausible strategy against Parkinson’s disease. As we recently demonstrated, the β-wrapin protein AS69 binds an N-terminal region in monomeric α-synuclein, interferes with fibril nucleation, and reduces α-synuclein aggregation in vitro and in a fruit fly model of α-synuclein toxicity. The aim of this study was to investigate whether AS69 also reduces α-synuclein pathology in mammalian neurons. To induce α-synuclein pathology, primary mouse neurons were exposed to pre-formed fibrils (PFF) of human α-synuclein. PFF were also injected into the striatum of A30P-α-synuclein transgenic mice. The extent of α-synuclein pathology was determined by phospho-α-synuclein staining and by Triton X-100 solubility. The degeneration of neuronal somata, dendrites, and axon terminals was determined by immunohistochemistry. AS69 and PFF were taken up by primary neurons. AS69 did not alter PFF uptake, but AS69 did reduce PFF-induced α-synuclein pathology. PFF injection into mouse striatum led to α-synuclein pathology and dystrophic neurites. Co-injection of AS69 abrogated PFF-induced pathology. AS69 also reduced the PFF-induced degeneration of dopaminergic axon terminals in the striatum and the degeneration of dopaminergic dendrites in the substantia nigra pars reticulata. AS69 reduced the activation of astroglia but not microglia in response to PFF injection. Collectively, AS69 reduced PFF-induced α-synuclein pathology and the associated neurodegeneration in primary neurons and in mouse brain. Our data therefore suggest that small proteins binding the N-terminus of α-synuclein monomers are promising strategies to modify disease progression in Parkinson’s disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A β-Wrapin Targeting the N-Terminus of α-Synuclein Monomers Reduces Fibril-Induced Aggregation in Neurons

et al. 2021

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“…( 55 ) as a region essential for aSyn filament assembly. Other groups have previously attempted to characterize aSyn aggregation hotspots ( 56 – 58 ), mainly using in silico approaches. These produced similar but not identical findings as the cell-based investigation performed here, which exploited functional analyses of single amino acid substitutions to produce a detailed empirical “aggregation map” of aSyn.…”

Section: Discussionmentioning

confidence: 99%

Saturation mutagenesis of α-synuclein reveals monomer fold that modulates aggregation

Chlebowicz,

Russ,

Chen

et al. 2023

Sci. Adv.

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α-Synuclein (aSyn) aggregation underlies neurodegenerative synucleinopathies. aSyn seeds are proposed to replicate and propagate neuronal pathology like prions. Seeding of aSyn can be recapitulated in cellular systems of aSyn aggregation; however, the mechanism of aSyn seeding and its regulation are not well understood. We developed an mEos-based aSyn seeding assay and performed saturation mutagenesis to identify with single-residue resolution positive and negative regulators of aSyn aggregation. We not only found the core regions that govern aSyn aggregation but also identified mutants outside of the core that enhance aggregation. We identified local structure within the N terminus of aSyn that hinders the fibrillization propensity of its aggregation-prone core. Based on the screen, we designed a minimal aSyn fragment that shows a ~4-fold enhancement in seeding activity and enabled discrimination of synucleinopathies. Our study expands the basic knowledge of aSyn aggregation and advances the design of cellular systems of aSyn aggregation to diagnose synucleinopathies based on protein conformation.

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“…The role of α-Syn amyloid fibrillation has been recognized in several neurological diseases including PD. In early stages, fibrillation occurs by a transition from a helical structure to extended states in monomeric α-Syn, followed by the formation of β-sheets [ 173 ]. This α-helix to β-sheet transition promotes the formation of amyloid fibrils by generating unstable and temporary α-Syn configurations.…”

Section: Lpls and Ndsmentioning

confidence: 99%

Lysophospholipids: A Potential Drug Candidates for Neurodegenerative Disorders

et al. 2022

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Neurodegenerative diseases (NDs) commonly present misfolded and aggregated proteins. Considerable research has been performed to unearth the molecular processes underpinning this pathological aggregation and develop therapeutic strategies targeting NDs. Fibrillary deposits of α-synuclein (α-Syn), a highly conserved and thermostable protein, are a critical feature in the development of NDs such as Alzheimer’s disease (AD), Lewy body disease (LBD), Parkinson’s disease (PD), and multiple system atrophy (MSA). Inhibition of α-Syn aggregation can thus serve as a potential approach for therapeutic intervention. Recently, the degradation of target proteins by small molecules has emerged as a new therapeutic modality, gaining the hotspot in pharmaceutical research. Additionally, interest is growing in the use of food-derived bioactive compounds as intervention agents against NDs via functional foods and dietary supplements. According to reports, dietary bioactive phospholipids may have cognition-enhancing and neuroprotective effects, owing to their abilities to influence cognition and mental health in vivo and in vitro. However, the mechanisms by which lipids may prevent the pathological aggregation of α-Syn warrant further clarification. Here, we review evidence for the potential mechanisms underlying this effect, with a particular focus on how porcine liver decomposition product (PLDP)-derived lysophospholipids (LPLs) may inhibit α-Syn aggregation.

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The hot sites of α-synuclein in amyloid fibril formation

Cited by 11 publications

References 66 publications

A β-Wrapin Targeting the N-Terminus of α-Synuclein Monomers Reduces Fibril-Induced Aggregation in Neurons

A β-Wrapin Targeting the N-Terminus of α-Synuclein Monomers Reduces Fibril-Induced Aggregation in Neurons

Saturation mutagenesis of α-synuclein reveals monomer fold that modulates aggregation

Lysophospholipids: A Potential Drug Candidates for Neurodegenerative Disorders

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