Molecular dynamics simulation reveals that switchable combinations of β-sheets underlie the prion-like properties of α-synuclein amyloids DOI Open Access
Hiroki Otaki, Yuzuru Taguchi, Noriyuki Nishida

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2018, Volume and Issue: unknown

Published: May 20, 2018

Abstract Diversity of prion strains is one the most mysterious traits prions because they are mere aggregates abnormally-folded forms single protein species, (PrP Sc ), without genome. Although strain-specific properties hypothesized to be enciphered in structures PrP instead nucleotide genome, specifically what structure can code information remains an enigma due incompatibility with structural analyses. strain diversity was regarded as unique prions, recently other disease-associated amyloids α-synuclein (αSyn) or tau also reported have “strains”. As detailed αSyn amyloid already identified and mutant associated familial Parkinson’s diseases, e.g. A53T, H50Q, G51D, been characterized, structure-phenotype relations this type could investigated by using a model. Here we intensively molecular dynamics simulation characterize influences mutations on homo- hetero-oligomer stacks amyloid. The simulations revealed directionality stack, remote effects distant β-sheets, existence at least two switchable interfaces/amyloid cores, distinct hetero-oligomerization depending mutation types. Collectively, those findings implied possible mechanism which multiple in-register parallel β-sheets side-by-side, support view that their prion-like inherent characteristic structures. We expect notion applicable .

Language: Английский

Effect of Disease-Associated P123H and V70M Mutations on β-Synuclein Fibrillation DOI
Karan Sharma, Surabhi Mehra,

Ajay Singh Sawner

et al.

ACS Chemical Neuroscience, Journal Year: 2020, Volume and Issue: 11(18), P. 2836 - 2848

Published: Aug. 24, 2020

Synucleinopathies are a class of neurodegenerative diseases, including Parkinson's disease (PD), Dementia with Lewy bodies (DLB), and Multiple System Atrophy (MSA). The common pathological hallmark synucleinopathies is the filamentous α-synuclein (α-Syn) aggregates along membrane components in cytoplasmic inclusions brain. β-Synuclein (β-Syn), an isoform α-Syn, inhibits α-Syn aggregation prevents its neurotoxicity, suggesting neuroprotective nature β-Syn. However, this notion changed discovery disease-associated β-Syn mutations, V70M P123H, patients DLB. It still unclear how these missense mutations alter structural amyloidogenic properties β-Syn, leading to neurodegeneration. Here, we characterized biophysical investigated effect on fibrillation under different conditions. P123H show high binding affinity compared wild-type their potential role interactions. mutants do not aggregate normal physiological conditions; however, proteins undergo self-polymerization slightly acidic microenvironment and/or presence inducer, forming long unbranched amyloid fibrils similar α-Syn. Strikingly, exhibit accelerated native NMR study further revealed that point induce local perturbations at site mutation Overall, our data provide insight into demonstrate make protein more susceptible altered microenvironment.

Language: Английский

Citations

12
Age-Related Changes of the Synucleins Profile in the Mouse Retina DOI Creative Commons

Sarah Batista Dias,

Luísa de Lemos,

Luís Sousa

et al.

Biomolecules, Journal Year: 2023, Volume and Issue: 13(1), P. 180 - 180

Published: Jan. 15, 2023

Alpha-synuclein (aSyn) plays a central role in Parkinson’s disease (PD) and has been extensively studied the brain. This protein is part of synuclein family, which also composed beta-synuclein (bSyn) gamma-synuclein (gSyn). In addition to its neurotoxic role, synucleins have important functions nervous system, modulating synaptic transmission. Synucleins are expressed retina, but they poorly characterized. However, there evidence that for visual function can play retinal degeneration. study aimed profile retina naturally aged mice correlate their patterns with specific cells. With aging, we observed decrease thickness layers, accompanied by an increase glial reactivity. Moreover, aSyn levels decreased, whereas bSyn increased aging. The colocalization both proteins was decreased inner plexiform layer (IPL) retina. gSyn presented age-related at nuclear not significantly changed ganglion cell layer. marker synaptophysin shown be preferentially colocalized IPL At same time, found exist presynaptic endings bipolar cells affected Overall, this suggests physiological aging responsible changes tissue, implicating functional alterations could affect family function.

Language: Английский

Citations

4
Investigating the neuroprotective effect of AAV-mediated β-synuclein overexpression in a transgenic model of synucleinopathy DOI Creative Commons

Dorian Sargent,

Dominique Bétemps,

Matthieu Drouyer

et al.

Scientific Reports, Journal Year: 2018, Volume and Issue: 8(1)

Published: Nov. 27, 2018

Abstract Parkinson’s disease (PD) and multiple system atrophy (MSA) are neurodegenerative diseases characterized by inclusions mainly composed of α-synuclein (α-syn) aggregates. The objective this study was to investigate if β-synuclein (β-syn) overexpression could have beneficial effects inhibiting the aggregation α-syn. M83 transgenic mouse is a model synucleinopathy, which develops severe motor symptoms associated with neonate or adult mice were injected adeno-associated virus vectors carrying human β-syn gene (AAVβ-syn) green fluorescent protein (AAVGFP) using different injection sites. - not accelerated extracts brains brain extract from (M83) origins. AAV expression confirmed Western blot ELISA technics. mediated did delay onset reduce α-syn phosphorylated at serine 129 levels detected ELISA, regardless route inoculation extracts. Instead, proteinase-K resistant staining immunohistochemistry, specifically in sick overexpressing after AAVβ-syn. This indicated for first time that viral vector-mediated form aggregates synucleinopathy.

Language: Английский

Citations

7
Inhibiting the fibrillation of a GLP-1-like peptide DOI

Raphael Egbu,

Christopher F. van der Walle, Steve Brocchini

et al.

International Journal of Pharmaceutics, Journal Year: 2019, Volume and Issue: 574, P. 118923 - 118923

Published: Dec. 5, 2019

Language: Английский

Citations

7
Molecular dynamics simulation reveals that switchable combinations of β-sheets underlie the prion-like properties of α-synuclein amyloids DOI Open Access
Hiroki Otaki, Yuzuru Taguchi, Noriyuki Nishida

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2018, Volume and Issue: unknown

Published: May 20, 2018

Abstract Diversity of prion strains is one the most mysterious traits prions because they are mere aggregates abnormally-folded forms single protein species, (PrP Sc ), without genome. Although strain-specific properties hypothesized to be enciphered in structures PrP instead nucleotide genome, specifically what structure can code information remains an enigma due incompatibility with structural analyses. strain diversity was regarded as unique prions, recently other disease-associated amyloids α-synuclein (αSyn) or tau also reported have “strains”. As detailed αSyn amyloid already identified and mutant associated familial Parkinson’s diseases, e.g. A53T, H50Q, G51D, been characterized, structure-phenotype relations this type could investigated by using a model. Here we intensively molecular dynamics simulation characterize influences mutations on homo- hetero-oligomer stacks amyloid. The simulations revealed directionality stack, remote effects distant β-sheets, existence at least two switchable interfaces/amyloid cores, distinct hetero-oligomerization depending mutation types. Collectively, those findings implied possible mechanism which multiple in-register parallel β-sheets side-by-side, support view that their prion-like inherent characteristic structures. We expect notion applicable .

Language: Английский

Citations

6