Detrimental effects of soluble α-synuclein oligomers at excitatory glutamatergic synapses DOI Creative Commons
Elena Ferrari, Michela Salvadè,

Elisa Zianni

et al.

Frontiers in Aging Neuroscience, Journal Year: 2023, Volume and Issue: 15

Published: March 16, 2023

Introduction Oligomeric and fibrillar species of the synaptic protein α-synuclein are established key players in pathophysiology Parkinson’s disease other synucleinopathies. Increasing evidence literature points to prefibrillar oligomers as main cytotoxic driving dysfunction diverse neurotransmitter systems even at early stages. Of note, soluble have recently been shown alter plasticity mechanisms glutamatergic cortico-striatal synapse. However, molecular morphological detrimental events triggered by aggregates that ultimately lead excitatory failure remain mostly elusive. Methods In present study, we aimed clarify effects (sOligo) synucleinopathies hippocampal synapses. To investigate defects striatal synapse vivo , sOligo were inoculated dorsolateral striatum 2-month-old wild-type C57BL/6J mice, analyses conducted 42 84 days post-injection. parallel, primary cultures rat neurons exposed sOligo, performed after 7 treatment. Results injection impaired post-synaptic retention ionotropic glutamate receptors decreased levels phosphorylated ERK These not correlated with alterations dendritic spines. Conversely, chronic vitro administration caused a significant decrease phosphorylation but did significantly or spine density neurons. Conclusion Overall, our data indicate involved pathogenic changes synapse, confirming effect these an synucleinopathy model. Moreover, affects signaling pathway similarly neurons, possibly representing mechanism anticipates loss.

Language: Английский

Role of α-synuclein in microglia: autophagy and phagocytosis balance neuroinflammation in Parkinson’s disease DOI

Qiankun Lv,

Kang‐Xin Tao,

Xiaobo Wang

et al.

Inflammation Research, Journal Year: 2023, Volume and Issue: 72(3), P. 443 - 462

Published: Jan. 4, 2023

Language: Английский

Citations

50
Protein Misfolding and Aggregation in Proteinopathies: Causes, Mechanism and Cellular Response DOI Creative Commons

Mohammad Ajmal

Diseases, Journal Year: 2023, Volume and Issue: 11(1), P. 30 - 30

Published: Feb. 9, 2023

Proteins are central to life functions. Alterations in the structure of proteins reflected their function. Misfolded and aggregates present a significant risk cell. Cells have diverse but integrated network protection mechanisms. Streams misfolded that cells continuously exposed must be continually monitored by an elaborated molecular chaperones protein degradation factors control contain misfolding problems. Aggregation inhibition properties small molecules such as polyphenols important they possess other beneficial antioxidative, anti-inflammatory, pro-autophagic help neuroprotection. A candidate with desired features is for any possible treatment development aggregation diseases. There need study phenomenon so we can treat some worst kinds human ailments related aggregation.

Language: Английский

Citations

46
Cathepsin B prevents cell death by fragmentation and destruction of pathological amyloid fibrils DOI Creative Commons
Maksim I. Sulatsky, Olesya V. Stepanenko, Olga V. Stepanenko

et al.

Cell Death Discovery, Journal Year: 2025, Volume and Issue: 11(1)

Published: Feb. 15, 2025

Amyloid fibrils cause organ and tissue dysfunction in numerous severe diseases. Despite the prevalence severity of amyloidoses, there is still no effective safe anti-amyloid therapy. This study investigates impact cysteine protease cathepsin B (CTSB) on amyloids associated with Alzheimer's Parkinson's diseases, hemodialysis, lysozyme amyloidosis. We analyzed effect CTSB size, structure, proteotoxicity amyloid formed from alpha-synuclein, abeta peptide (1-42), insulin, using a combination spectroscopic, microscopic, electrophoretic, colorimetric methods. Our comprehensive research revealed dual fibrils. Firstly, induced fragmentation while preserving their ordered morphology, and, secondly, it "loosened" tertiary structure reduced regularity secondary structure. mechanism action was universal across different pathologies, although disruption efficacy predominant type degradation products depended amyloids' clustering. Notably, CTSB-induced irreversible significantly toxicity for immortalized primary cell lines low-clustered fibrils, such as alpha-synuclein disease. These findings enhance our understanding how endogenous may regulate content at molecular level neuropathologies. In addition, results suggest potential component drugs agents that accessibility proteolytic sites within clots reduce these clusters stability.

Language: Английский

Citations

2
“Prion-like” seeding and propagation of oligomeric protein assemblies in neurodegenerative disorders DOI Creative Commons
Silvia Zampar, Sonja E. Di Gregorio,

Gustavo Grimmer

et al.

Frontiers in Neuroscience, Journal Year: 2024, Volume and Issue: 18

Published: Aug. 5, 2024

Intra- or extracellular aggregates of proteins are central pathogenic features in most neurodegenerative disorders. The accumulation such diseased brains is believed to be the end-stage a stepwise aggregation misfolded monomers insoluble cross-β fibrils via series differently sized soluble oligomers/protofibrils. Several studies have shown how α-synuclein, amyloid-β, tau and other amyloidogenic can act as nucleating particles thereby share properties with forms, strains, prion protein. Although roles different protein assemblies respective cascades remain unclear, oligomers/protofibrils considered key species. Numerous observations demonstrated their neurotoxic effects growing number indicated that they also possess seeding properties, enabling propagation within cellular networks nervous system. behavior oligomers differs between affected by various factors, size, shape epitope presentation. Here, we providing an overview current state knowledge respect “prion-like” for several involved diseases. In addition new insight into mechanisms, research this field leading novel diagnostic therapeutic opportunities

Language: Английский

Citations

4
Plasma β2-microglobulin and cerebrospinal fluid biomarkers of Alzheimer’s disease pathology in cognitively intact older adults: the CABLE study DOI Creative Commons
Yi‐Ming Huang,

Ya‐Hui Ma,

Pei‐Yang Gao

et al.

Alzheimer s Research & Therapy, Journal Year: 2023, Volume and Issue: 15(1)

Published: April 1, 2023

Abstract Background Previous studies have suggested a correlation between elevated levels of β 2 -microglobulin (B2M) and cognitive impairment. However, the existing evidence is insufficient to establish conclusive relationship. This study aims analyze link plasma B2M cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarkers cognition. Methods To track dynamics in preclinical AD, 846 cognitively healthy individuals Chinese Biomarker LifestylE (CABLE) cohort were divided into four groups (suspected non-AD pathology [SNAP], 2, 1, 0) according NIA-AA criteria. Multiple linear regression models employed examine B2M’s relationship with CSF AD biomarkers. Causal mediation analysis was conducted through 10,000 bootstrapped iterations explore mediating effect on Results We found that increased stages 1 ( P = 0.0007) < 0.0001), contrast stage 0. In total participants, higher associated worse performance 0.006 for MMSE; 0.012 MoCA). Moreover, level decreases Aβ 1–42 0.001) /Aβ 1–40 0.015) as well increases T-tau/Aβ P-tau/Aβ 0.001). The subgroup correlated non- APOE ε4 but not carriers. Additionally, cognition partially mediated by (percentage: 8.6 19.3%), whereas tau did mediate this effect. Conclusions demonstrated association possible important role impairment, particularly normal individuals. results indicated could be potential biomarker might varied functions throughout various progression.

Language: Английский

Citations

9
Modulation of AIE and Intramolecular Charge Transfer of a Pyrene-Based Probe for Discriminatory Detection and Imaging of Oligomers and Amyloid Fibrils DOI

Dharini Arumugam,

Nidhi Anilkumar Jamuna,

Adithya Kamalakshan

et al.

ACS Applied Bio Materials, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 18, 2024

Oligomers and amyloid fibrils formed at different stages of protein aggregation are important biomarkers for a variety neurodegenerative diseases including Alzheimer's Parkinson's diseases. The development probes the sensitive detection oligomeric species is early stage diagnosis amyloidogenic Many small molecular dyes have been developed to probe dynamic growth fibrils. However, there lack discriminatory strategies monitor dynamics both oligomers based on differential modulation photophysical properties single dye. Here we report pyrene-based intramolecular charge transfer (ICT) dye with large Stokes shifted red-emitting induced emission (AIE) monitoring populations during hen egg white lysozyme (HEWL) protein. At aggregation, accumulation HEWL results in rapid substantial increase red AIE intensity 660 nm. Later, as transform into mature fibrils, exhibits distinct change. Binding strongly suppresses enhances ICT emission. This evidenced by gradual decrease (∼660 nm) an LE (∼490 (∼540 intensities later aggregation. Thus, provides simultaneous measurements population also enables imaging simultaneously using channels super-resolution confocal fluorescence microscopy.

Language: Английский

Citations

3
α-Synuclein oligomers and fibrils: partners in crime in synucleinopathies DOI Creative Commons
Alessandra Bigi, Roberta Cascella, Cristina Cecchi

et al.

Neural Regeneration Research, Journal Year: 2023, Volume and Issue: 18(11), P. 2332 - 2342

Published: March 11, 2023

The misfolding and aggregation of α-synuclein is the general hallmark a group devastating neurodegenerative pathologies referred to as synucleinopathies, such Parkinson's disease, dementia with Lewy bodies, multiple system atrophy. In conditions, range different misfolded aggregates, including oligomers, protofibrils, fibrils, are present both in neurons glial cells. Growing experimental evidence supports proposition that soluble oligomeric assemblies, formed during early phases process, major culprits neuronal toxicity; at same time, fibrillar conformers appear be most efficient propagating among interconnected neurons, thus contributing spreading pathology. Moreover, fibrils have been recently reported release highly toxic species, responsible for an immediate dysfunction recipient neurons. this review, we discuss current knowledge about plethora mechanisms cellular caused by oligomers neurodegeneration synucleinopathies.

Language: Английский

Citations

8
The mechanistic interaction, aggregation and neurotoxicity of α-synuclein after interaction with glycyrrhizic acid: Modulation of synucleinopathies DOI

Luyang Zhang,

Na Zhang, Chao Pang

et al.

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 267, P. 131423 - 131423

Published: April 5, 2024

Language: Английский

Citations

2
α-Synuclein and biological membranes: the danger of loving too much DOI Creative Commons
S Mansueto, Giuliana Fusco, Alfonso De Simone

et al.

Chemical Communications, Journal Year: 2023, Volume and Issue: 59(57), P. 8769 - 8778

Published: Jan. 1, 2023

Membrane interactions are key for both the physiological and pathological forms of α-Synuclein (αS).

Language: Английский

Citations

6
Multistep molecular mechanisms of Aβ16-22 fibril formation revealed by lattice Monte Carlo simulations DOI
Phuong H. Nguyen, Philippe Derreumaux

The Journal of Chemical Physics, Journal Year: 2023, Volume and Issue: 158(23)

Published: June 15, 2023

As a model of self-assembly from disordered monomers to fibrils, the amyloid-β fragment Aβ16-22 was subject past numerous experimental and computational studies. Because dynamics information between milliseconds seconds cannot be assessed by both studies, we lack full understanding its oligomerization. Lattice simulations are particularly well suited capture pathways fibrils. In this study, explored aggregation 10 peptides using 65 lattice Monte Carlo simulations, each simulation consisting 3 × 109 steps. Based on total 24 41 that converge do not fibril state, respectively, able reveal diversity leading structure conformational traps slowing down formation.

Language: Английский

Citations

5