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

α-Synuclein misfolding and aggregation: Implications in Parkinson’s disease pathogenesis DOI
Surabhi Mehra,

Shruti Sahay,

Samir K. Maji

et al.

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Journal Year: 2019, Volume and Issue: 1867(10), P. 890 - 908

Published: March 7, 2019

Language: Английский

Citations

364
Multifaceted interactions mediated by intrinsically disordered regions play key roles in alpha synuclein aggregation DOI Open Access
Sagar D. Khare,

Priscilla Chinchilla,

Jean Baum

et al.

Current Opinion in Structural Biology, Journal Year: 2023, Volume and Issue: 80, P. 102579 - 102579

Published: April 13, 2023

Language: Английский

Citations

23
Metal ions shape α-synuclein DOI Creative Commons
Rani Moons, Albert Konijnenberg, Carl Mensch

et al.

Scientific Reports, Journal Year: 2020, Volume and Issue: 10(1)

Published: Oct. 1, 2020

Abstract α-Synuclein is an intrinsically disordered protein that can self-aggregate and plays a major role in Parkinson’s disease (PD). Elevated levels of certain metal ions are found aggregates neurons people suffering from PD, environmental exposure has also been linked with neurodegeneration. Importantly, cellular interactions ions, particularly Ca 2+ , have recently reported as key for α-synuclein’s physiological function at the pre-synapse. Here we study effects ion interaction α-synuclein molecular level, observing changes conformational behaviour monomers, possible link to aggregation pathways toxicity. Using native nano-electrospray ionisation mobility-mass spectrometry (nESI-IM-MS), characterize heterogeneous alkali, alkaline earth, transition other their global structural on α-synuclein. Different binding stoichiometries upon titration correlate specific affinity capacity. Subtle seen singly charged metals differ profoundly multiply often leading overall compaction depending preferred sites. This illustrates coordination, associated electrostatic charge patterns, complex space

Language: Английский

Citations

69
β-Synuclein: An Enigmatic Protein with Diverse Functionality DOI Creative Commons

Junna Hayashi,

John A. Carver

Biomolecules, Journal Year: 2022, Volume and Issue: 12(1), P. 142 - 142

Published: Jan. 16, 2022

α-Synuclein (αS) is a small, unstructured, presynaptic protein expressed in the brain. Its aggregated form major component of Lewy bodies, large proteinaceous deposits Parkinson's disease. The closely related protein, β-Synuclein (βS), co-expressed with αS. In vitro, βS acts as molecular chaperone to inhibit αS aggregation. As result this assignation, has been largely understudied comparison However, recent reports suggest that promotes neurotoxicity, implying involved other cellular pathways functions independent Here, we review current literature pertaining human order understand better role homeostasis and pathology. Firstly, structure discussed. Secondly, ability (i) act chaperone; (ii) regulate synaptic function, lipid binding, nigrostriatal dopaminergic system; (iii) mediate apoptosis; (iv) participate degradation pathways; (v) modulate intracellular metal levels; (vi) promote toxicity aggregation explored. Thirdly, P123H V70M mutations βS, which are associated dementia Finally, importance post-translational modifications on function reviewed. Overall, it concluded both synergistic antagonistic interactions αS, but may also possess important

Language: Английский

Citations

30
Substitution of Met-38 to Ile in γ-synuclein found in two patients with amyotrophic lateral sclerosis induces aggregation into amyloid DOI Creative Commons
Liam D. Aubrey, Natalia Ninkina, Sabine M. Ulamec

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(2)

Published: Jan. 3, 2024

α-, β-, and γ-Synuclein are intrinsically disordered proteins implicated in physiological processes the nervous system of vertebrates. α-synuclein (αSyn) is amyloidogenic protein associated with Parkinson’s disease certain other neurodegenerative disorders. Intensive research has focused on mechanisms that cause αSyn to form amyloid structures, identifying its NAC region as being necessary sufficient for assembly. Recent work shown a 7-residue sequence (P1) formation. Although γ-synuclein (γSyn) 55% identical pathological deposits also observed association conditions, γSyn resilient formation vitro. Here, we report rare single nucleotide polymorphism (SNP) SNCG gene encoding γSyn, found two patients amyotrophic lateral sclerosis (ALS). The SNP results substitution Met38 Ile P1 protein. These individuals had second, common nonpathological, resulting Glu110 Val. In vitro studies demonstrate Ile38 variant accelerates fibril Contrastingly, Val110 retards assembly mitigates effect Ile38. Substitution residue 38 Leu little effect, while Val retards, Ala increases rate γSyn-containing inclusions cells. show how point can enhance highlight driving another synuclein family member.

Language: Английский

Citations

6
Kinetic barriers to α-synuclein protofilament formation and conversion into mature fibrils DOI Creative Commons
James W. Brown, Georg Meisl, Tuomas P. J. Knowles

et al.

Chemical Communications, Journal Year: 2018, Volume and Issue: 54(56), P. 7854 - 7857

Published: Jan. 1, 2018

An increase in temperature allows the conversion of α-synuclein lipid-induced proto-fibrils to mature fibrils by overcoming associated energy barrier.

Language: Английский

Citations

39
Antioxidant Nanoparticles for Concerted Inhibition of α-Synuclein Fibrillization, and Attenuation of Microglial Intracellular Aggregation and Activation DOI Creative Commons
Nanxia Zhao, Xue Yang, Hannah Calvelli

et al.

Frontiers in Bioengineering and Biotechnology, Journal Year: 2020, Volume and Issue: 8

Published: Feb. 21, 2020

Parkinson's Disease is characterized by the loss of dopaminergic neurons in substantia nigra pars compacta, extracellular accumulation toxic α-synuclein (αSYN) aggregates, and neuroinflammation. Microglia, resident macrophages brain, are one critical cell types involved Upon sensing stimuli or experiencing oxidative stress, microglia become activated, which further exacerbates In addition, as first line defense central nervous system, play a role αSYN clearance degradation. While neurodegenerative pathologies widely recognized, few therapeutic approaches have been designed to target both microglial activation aggregation. Here, we nanoparticles (NPs) deliver aggregation-inhibiting antioxidants ameliorate aggregation attenuate pro-inflammatory phenotype. Ferulic acid diacid with an adipic linker (FAA) tannic (TA) were used shell core molecules form NPs via flash nanoprecipitation. These showed strong inhibitory effect on fibrillization, significantly diminishing fibrillization vitro compared untreated using Thioflavin T assay. Treating decreased overall internalization intracellular oligomer formation. NP treatment additionally lowered secretion cytokines TNF-α IL-6, also attenuated nitric oxide reactive oxygen species production induced αSYN. Iba-1 expression αSYN-challenged suppressed nuclear translocation factor kappa B (NF-κB). Overall, this work lays foundation for antioxidant-based nanotherapeutic candidate pathological protein neuroinflammation diseases.

Language: Английский

Citations

39
Alternative Splicing of Alpha- and Beta-Synuclein Genes Plays Differential Roles in Synucleinopathies DOI Open Access
Ana Gámez‐Valero, Katrin Beyer

Genes, Journal Year: 2018, Volume and Issue: 9(2), P. 63 - 63

Published: Jan. 25, 2018

The synuclein family is composed of three members, two which, α- and β-synuclein, play a major role in the development synucleinopathies, including Parkinson’s disease (PD) as most important movement disorder, dementia with Lewy bodies (DLB) second frequent cause after Alzheimer’s multiple system atrophy. Whereas abnormal oligomerization fibrillation α-synuclein are now well recognized initial steps β-synuclein thought to be natural anti-aggregant. encoded by SNCA gene, SNCB. Both genes homologous undergo complex splicing events. On one hand, in-frame coding exons gives rise at least shorter transcripts, functional properties corresponding protein isoforms different. Another type alternative inclusion four case SNCA, Finally, different lengths 3’ untranslated regions have been also reported for both genes. SNCB only expresses brain, but some numerous transcripts brain-specific. With present article, we aim provide systematic review related changes differential expression various transcript variants blood, non-neuronal tissue especially PD DLB neurodegenerative disorders.

Language: Английский

Citations

37
pH-Dependent fibril maturation of a Pmel17 repeat domain isoform revealed by tryptophan fluorescence DOI
Dexter N. Dean, Jennifer C. Lee

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Journal Year: 2019, Volume and Issue: 1867(10), P. 961 - 969

Published: Feb. 1, 2019

Language: Английский

Citations

33
pH Induced Switch in the Conformational Ensemble of Intrinsically Disordered Protein Prothymosin-α and Its Implications for Amyloid Fibril Formation DOI
Lipika Baidya, Govardhan Reddy

The Journal of Physical Chemistry Letters, Journal Year: 2022, Volume and Issue: 13(41), P. 9589 - 9598

Published: Oct. 7, 2022

Aggregation of intrinsically disordered proteins (IDPs) can lead to neurodegenerative diseases. Although there is experimental evidence that acidic pH promotes IDP monomer compaction leading aggregation, the general mechanism unclear. We studied effect on conformational ensemble prothymosin-α (proTα), which involved in multiple essential functions, and probed its role aggregation using computer simulations. show proTα dimension at low due protein's collapse intermediate region (E41-D80) rich glutamic acid residues, enhancing β-sheet content. observed by performing dimer simulations conformations with high content could act as aggregation-prone (N*) states nucleate process. The initiated N* form dimers within a microsecond time scale, whereas non-N* do not this scale. This study contributes understanding principles pH-induced aggregation.

Language: Английский

Citations

17