Role of neuroinflammation in neurodegeneration development

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: July 12, 2023

Abstract Studies in neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and Amyotrophic lateral sclerosis, Huntington’s so on, have suggested that inflammation is not only a result of neurodegeneration but also crucial player this process. Protein aggregates which are very common pathological phenomenon can induce neuroinflammation further aggravates protein aggregation neurodegeneration. Actually, even happens earlier than aggregation. Neuroinflammation induced by genetic variations CNS cells or peripheral immune may deposition some susceptible population. Numerous signaling pathways range been to be involved the pathogenesis neurodegeneration, although they still far from being completely understood. Due limited success traditional treatment methods, blocking enhancing inflammatory considered promising strategies for therapy many them got exciting results animal models clinical trials. Some them, few, approved FDA usage. Here we comprehensively review factors affecting major pathogenicity sclerosis. We summarize current strategies, both clinic, diseases.

Language: Английский

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α-Synuclein in synaptic function and dysfunction

Trends in Neurosciences, Journal Year: 2022, Volume and Issue: 46(2), P. 153 - 166

Published: Dec. 23, 2022

Language: Английский

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How phosphorylation impacts intrinsically disordered proteins and their function

Essays in Biochemistry, Journal Year: 2022, Volume and Issue: 66(7), P. 901 - 913

Published: Nov. 9, 2022

Abstract Phosphorylation is the most common post-translational modification (PTM) in eukaryotes, occurring particularly frequently intrinsically disordered proteins (IDPs). These are highly flexible and dynamic by nature. Thus, it intriguing that addition of a single phosphoryl group to chain can impact its function so dramatically. Furthermore, as many IDPs carry multiple phosphorylation sites, number possible states increases, enabling larger complexities novel mechanisms. Although chemically simple well-understood process, on conformational ensemble molecular IDPs, not mention biological output, complex diverse. Since discovery first site 75 years ago, we have come much better understanding how this PTM works, but with diversity their capacity for carrying groups, complexity grows. In Essay, highlight some basic effects IDP phosphorylation, allowing serve starting point when embarking studies into topic. We further describe recent cases multisite been instrumental widening our view effect protein phosphorylation. Finally, put forward perspectives both relation disease context other PTMs; areas where deep insight remains be uncovered.

Language: Английский

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Current Technologies Unraveling the Significance of Post-Translational Modifications (PTMs) as Crucial Players in Neurodegeneration

Biomolecules, Journal Year: 2024, Volume and Issue: 14(1), P. 118 - 118

Published: Jan. 16, 2024

Neurodegenerative disorders, such as Parkinson’s disease, Alzheimer’s and Huntington’s are identified characterized by the progressive loss of neurons neuronal dysfunction, resulting in cognitive motor impairment. Recent research has shown importance PTMs, phosphorylation, acetylation, methylation, ubiquitination, sumoylation, nitration, truncation, O-GlcNAcylation, hydroxylation, progression neurodegenerative disorders. PTMs can alter protein structure function, affecting stability, localization, interactions, enzymatic activity. Aberrant lead to misfolding aggregation, impaired degradation, clearance, ultimately, dysfunction death. The main objective this review is provide an overview involved neurodegeneration, their underlying mechanisms, methods isolate potential therapeutic targets for these discussed article include tau α-synuclein Huntingtin histone acetylation RNA modifications. Understanding role diseases may new strategies devastating

Language: Английский

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Neurodegenerative diseases and catechins: (−)-epigallocatechin-3-gallate is a modulator of chronic neuroinflammation and oxidative stress

Frontiers in Nutrition, Journal Year: 2024, Volume and Issue: 11

Published: Aug. 1, 2024

Catechins, a class of phytochemicals found in various fruits and tea leaves, have garnered attention for their diverse health-promoting properties, including potential combating neurodegenerative diseases. Among these catechins, (-)-epigallocatechin-3-gallate (EGCG), the most abundant polyphenol green tea, has emerged as promising therapeutic agent due to its potent antioxidant anti-inflammatory effects. Chronic neuroinflammation oxidative stress are key pathological mechanisms diseases such Alzheimer's disease (AD) Parkinson's (PD). EGCG neuroprotective efficacy scavenging free radicals, reducing attenuating neuroinflammatory processes. This review discusses molecular EGCG's anti-oxidative chronic neuroinflammation, emphasizing effects on autoimmune responses, neuroimmune system interactions, focusing related AD PD. By elucidating action impact processes, this underscores intervention AD, PD, possibly other Overall, emerges natural compound stress, offering novel avenues strategies treatment disorders.

Language: Английский

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Fasudil inhibits α-synuclein aggregation through ROCK-inhibition-mediated mechanisms

Neurotherapeutics, Journal Year: 2025, Volume and Issue: unknown, P. e00544 - e00544

Published: Feb. 1, 2025

ROCK inhibitors such as fasudil protected against dopaminergic degeneration and other neurodegenerative processes in several experimental models through inhibition of neuroinflammation activation survival signaling pathways, clinical trials have been initiated. More recently, has suggested to inhibit α-synuclein aggregation. However, this is controversial, particularly if it a consequence direct binding the molecule α-synuclein. We studied mechanisms involved effects on aggregation using α-synuclein-T/V5-synphilin-1 model. Molecule-molecule interactions were real time quaking inducing conversion (RT-QuiC). Fasudil decreased number cells with inclusions size neurons glial cells, inhibited microglial endocytosis aggregates. These changes not due protein expression or phosphorylation related rather than interaction α-synuclein, confirmed second inhibitor (Y27632) gene silencing. observed that downregulates factors are known promote NADPH-oxidase-derived oxidative stress, intracellular calcium increase, endocytosis, promotes autophagy. The present results support useful drug Parkinson's disease progression. In addition reported neuroprotective properties, inhibits aggregates, which enhances inflammatory response. mostly inhibition, we shown two structurally different knockdown data, further supported by RT-QuiC.

Language: Английский

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Experimental Evidence for Phosphorylation-Driven Allosteric Regulation of Alpha Synuclein Function

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 26, 2025

Phosphorylation of serine 129 (pS129) in the intrinsically disordered protein alpha synuclein has long been associated with neurodegenerative disease. In past several years, functional relevance pS219 uncovered by electrophysiology, immunoprecipitation, and proteomics as intricately connected neurotransmitter release synaptic vesicle (SV) cycling. Unexpectedly, binding to SNARE complex proteins VAMP-2 synapsin only occurs phosphorylation-competent synuclein. The domain shown be residues 96-110, which does not include phosphorylated residue, hinting at allosteric regulation protein-protein interactions pS129. Within this study, cross-linking, covalent labeling, collision induced unfolding pS129 - well an additional encountered form brain, oxidized-M1, M5, M116, M127 are studied utilizing tandem mass spectrometry. Collision gives a fingerprint structures' relative compactness stabilities various conformations. Covalent labeling identifies solvent accessible reveals hydrophobicity (or hydrophilicity) their microenvironment, while cross-linking maps proximity residue pairs. combination unfolding, show unequivocally that phosphorylated-S129 results more stable, compact form. Our provide evidence extensively folded amphipathic region interacts strongly domain. phosphorylation-induced folding likely tunes other SVs membranes.

Language: Английский

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A novel integrative multimodal classifier to enhance the diagnosis of Parkinson’s disease

Briefings in Bioinformatics, Journal Year: 2025, Volume and Issue: 26(2)

Published: March 1, 2025

Abstract Parkinson’s disease (PD) is a complex, progressive neurodegenerative disorder with high heterogeneity, making early diagnosis difficult. Early detection and intervention are crucial for slowing PD progression. Understanding PD’s diverse pathways mechanisms key to advancing knowledge. Recent advances in noninvasive imaging multi-omics technologies have provided valuable insights into underlying causes biological processes. However, integrating these data sources remains challenging, especially when deriving meaningful low-level features that can serve as diagnostic indicators. This study developed validated novel integrative, multimodal predictive model detecting based on derived from data, including hematological information, proteomics, RNA sequencing, metabolomics, dopamine transporter scan imaging, sourced the Progression Markers Initiative. Several architectures were investigated evaluated, support vector machine, eXtreme Gradient Boosting, fully connected neural networks concatenation joint modeling (FCNN_C FCNN_JM), encoder-based multi-head cross-attention (MMT_CA). The MMT_CA demonstrated superior performance, achieving balanced classification accuracy of 97.7%, thus highlighting its ability capture leverage cross-modality inter-dependencies aid analytics. Furthermore, feature importance analysis using SHapley Additive exPlanations not only identified biomarkers inform models this but also holds potential future research aimed at integrated functional analyses perspective, ultimately revealing targets required precision medicine approaches treatment down

Language: Английский

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Functional and Pathological Effects of α-Synuclein on Synaptic SNARE Complexes

Journal of Molecular Biology, Journal Year: 2022, Volume and Issue: 435(1), P. 167714 - 167714

Published: July 3, 2022

Language: Английский

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Angiotensin type 1 receptor activation promotes neuronal and glial alpha-synuclein aggregation and transmission

npj Parkinson s Disease, Journal Year: 2024, Volume and Issue: 10(1)

Published: Feb. 17, 2024

Abstract The brain renin-angiotensin system (RAS) has been related to dopaminergic degeneration, and high expression of the angiotensin II (AngII) type 1 receptor (AT1) gene is a marker most vulnerable neurons in humans. However, it unknown whether AngII/AT1 overactivation affects α-synuclein aggregation transmission. In vitro, activation increased microglial cells, which was AngII-induced NADPH-oxidase intracellular calcium raising. mice, involved MPTP-induced increase aggregation, as they significantly decreased mice treated with AT1 blocker telmisartan knockout mice. Cell co-cultures (transwells) revealed strong transmission from astrocytes microglia. AngII induced higher uptake by cells an transfer among astroglial cells. did not release neurons. results further support RAS dysregulation major mechanism for progression Parkinson’s disease, inhibition modulation therapeutic targets.

Language: Английский

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