Alpha Synuclein: Neurodegeneration and Inflammation

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(6), С. 5914 - 5914

Опубликована: Март 21, 2023

Alpha-Synuclein (α-Syn) is one of the most important molecules involved in pathogenesis Parkinson’s disease and related disorders, synucleinopathies, but also several other neurodegenerative disorders with a more elusive role. This review analyzes activities α-Syn, different conformational states, monomeric, oligomeric fibrils, relation to neuronal dysfunction. The damage induced by α-Syn various conformers will be analyzed its capacity spread intracellular aggregation seeds prion-like mechanism. In view prominent role inflammation virtually all activity illustrated considering influence on glial reactivity. We others have described interaction between general cerebral dysfunctional α-Syn. Differences microglia astrocyte activation been observed when vivo presence oligomers has combined lasting peripheral inflammatory effect. reactivity was amplified, while astrocytes were damaged double stimulus, opening new perspectives for control synucleinopathies. Starting from our studies experimental models, we extended perspective find useful pointers orient future research potential therapeutic strategies disorders.

Язык: Английский

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New Pathways Identify Novel Drug Targets for the Prevention and Treatment of Alzheimer’s Disease

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(6), С. 5383 - 5383

Опубликована: Март 11, 2023

Alzheimer’s disease (AD) is an incurable, progressive neurodegenerative disorder. AD a complex and multifactorial that responsible for 60–80% of dementia cases. Aging, genetic factors, epigenetic changes are the main risk factors AD. Two aggregation-prone proteins play decisive role in pathogenesis: β-amyloid (Aβ) hyperphosphorylated tau (pTau). Both them form deposits diffusible toxic aggregates brain. These biomarkers Different hypotheses have tried to explain pathogenesis served as platforms drug research. Experiments demonstrated both Aβ pTau might start processes necessary cognitive decline. The two pathologies act synergy. Inhibition formation has been old target. Recently, successful clearance by monoclonal antibodies raised new hopes treatments if detected at early stages. More recently, novel targets, e.g., improvements amyloid from brain, application small heat shock (Hsps), modulation chronic neuroinflammation different receptor ligands, microglial phagocytosis, increase myelination revealed

Язык: Английский

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Functional Amyloids: Where Supramolecular Amyloid Assembly Controls Biological Activity or Generates New Functionality

Journal of Molecular Biology, Год журнала: 2023, Номер 435(11), С. 167919 - 167919

Опубликована: Июнь 1, 2023

Язык: Английский

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Cryo-EM observation of the amyloid key structure of polymorphic TDP-43 amyloid fibrils

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Янв. 12, 2024

Abstract The transactive response DNA-binding protein-43 (TDP-43) is a multi-facet protein involved in phase separation, RNA-binding, and alternative splicing. In the context of neurodegenerative diseases, abnormal aggregation TDP-43 has been linked to amyotrophic lateral sclerosis frontotemporal lobar degeneration through its C-terminal domain. Here, we report cryo-electron microscopy (cryo-EM)-based structural characterization fibrils obtained from full-length protein. We find that are polymorphic contain three different amyloid structures. structures differ number relative orientation protofilaments, although they share similar fold containing an key motif. observed fibril previously described conformations help better understand landscape derived this

Язык: Английский

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Structural insights into the role of reduced cysteine residues in SOD1 amyloid filament formation

Proceedings of the National Academy of Sciences, Год журнала: 2025, Номер 122(5)

Опубликована: Янв. 28, 2025

The formation of superoxide dismutase 1 (SOD1) filaments has been implicated in amyotrophic lateral sclerosis (ALS). Although the disulfide bond formed between Cys57 and Cys146 active state well studied, role reduced cysteine residues, Cys6 Cys111, SOD1 filament remains unclear. In this study, we investigated residues by determining comparing cryoelectron microscopy (cryo-EM) structures wild-type (WT) C6A/C111A under thiol-based reducing metal-depriving conditions, starting with protein samples possessing enzymatic activity. mutant more rapidly than WT protein. structure had a unique paired-protofilament arrangement, smaller core that single-protofilament observed SOD1. form developed slowly, cross-seeding experiments demonstrated predominance morphology over paired protofilaments, regardless presence Cys111 mutations. These findings highlight importance number amino acid within energy requirements for assembly. Our study provides insights into ALS pathogenesis elucidating initiation propagation formation, which potentially leads to deleterious amyloid filaments.

Язык: Английский

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In-depth investigation of the effect of pH on the autofluorescence properties of DPF3b and DPF3a amyloid fibrils

Spectrochimica Acta Part A Molecular and Biomolecular Spectroscopy, Год журнала: 2024, Номер 313, С. 124156 - 124156

Опубликована: Март 14, 2024

Язык: Английский

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Disease-relevant β2-microglobulin variants share a common amyloid fold

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Март 2, 2023

β2-microglobulin (β2m) and its truncated variant ΔΝ6 are co-deposited in amyloid fibrils the joints, causing disorder dialysis-related amyloidosis (DRA). Point mutations of β2m result diseases with distinct pathologies. β2m-D76N causes a rare systemic protein deposited viscera absence renal failure, whilst β2m-V27M is associated deposits forming predominantly tongue. Here we use cryoEM to determine structures formed from these variants under identical conditions vitro. We show that each fibril sample polymorphic, diversity arising 'lego-like' assembly common building block. These results suggest 'many sequences, one fold' paradigm contrast recently reported 'one sequence, many folds' behaviour intrinsically disordered proteins such as tau Aβ.

Язык: Английский

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Application of Amyloid-Based Hybrid Membranes in Drug Delivery

Polymers, Год журнала: 2023, Номер 15(6), С. 1444 - 1444

Опубликована: Март 14, 2023

The properties of amyloid fibrils, e.g., unique structural characteristics and superior biocompatibility, make them a promising vehicle for drug delivery. Here, carboxymethyl cellulose (CMC) whey protein isolate fibril (WPI-AF) were used to synthesize amyloid-based hybrid membranes as vehicles the delivery cationic hydrophobic drugs (e.g., methylene blue (MB) riboflavin (RF)). CMC/WPI-AF synthesized via chemical crosslinking coupled with phase inversion. zeta potential scanning electron microscopy results revealed negative charge pleated surface microstructure high content WPI-AF. FTIR analysis showed that CMC WPI-AF cross-linked glutaraldehyde interacting forces between membrane MB or RF was found be electrostatic interaction hydrogen bonding, respectively. Next, in vitro release from monitored using UV-vis spectrophotometry. Additionally, two empirical models analyze data relevant rate constant parameters determined accordingly. Moreover, our indicated rates depended on drug–matrix interactions transport mechanism, which could controlled by altering membrane. This research provides an excellent example utilizing two-dimensional materials

Язык: Английский

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Amyloids in bladder cancer hijack cancer-related proteins and are positive correlated to tumor stage

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Фев. 5, 2025

Despite the current diagnostic and therapeutic approaches to bladder cancer being widely accepted, there have been few significant advancements in this field over past decades. This underscores necessity for a paradigm shift approach cancer. The role of amyloids remains unclear despite their identification several other pathologies. In study, we present evidence cancer, both vitro vivo. murine model positive correlation was observed between tumor stage, indicating an association progression. Subsequently, amyloid proteome RT4 non-invasive HT1197 invasive cell lines identified included oncogenes, suppressors, highly expressed cancer-related proteins. It is proposed that function as structures sequester key Therefore, should be considered study diagnosis

Язык: Английский

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Kinetic Steering of Amyloid Formation and Polymorphism by Canagliflozin, a Type-2 Diabetes Drug

Journal of the American Chemical Society, Год журнала: 2025, Номер unknown

Опубликована: Фев. 21, 2025

Amyloid formation is involved in widespread health conditions such as Alzheimer's disease, Parkinson's and type-2 diabetes. fibrils have a similar cross-β architecture, but formed by single protein sequence can diverse structures, varying with time, self-assembly conditions, modifications. Fibril structure has been proposed to be diagnostic of why different structures result under especially vitro, remains elusive. We previously identified small molecule, YX-I-1, which inhibits vitro amyloid islet polypeptide (IAPP), peptide hormone whose Here, using YX-I-1 lead, we regulator-approved drugs chemical similarity analysis substructure searches monitored the effect 24 these potential ligands on IAPP assembly vitro. show that one compound, canagliflozin (Invokana), diabetes drug already clinical use, strongly delay kinetics formation, an activity independent its intended mode action [sodium-glucose linked transporter 2 (SGLT2) inhibitor] may important therapeutic implications. Combining kinetics, biophysical characterization monomer fibril binding, cryo-EM products, target early aggregation, remodeling energy landscape primary nucleation profoundly altering resulting structures. Early binding events thus imprint long-lasting effects form.

Язык: Английский

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