α-Synuclein pathology as a target in neurodegenerative diseases

Nature Reviews Neurology, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 28, 2024

Язык: Английский

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Alpha-Synuclein Effects on Mitochondrial Quality Control in Parkinson’s Disease

Biomolecules, Год журнала: 2024, Номер 14(12), С. 1649 - 1649

Опубликована: Дек. 22, 2024

The maintenance of healthy mitochondria is essential for neuronal survival and relies upon mitochondrial quality control pathways involved in biogenesis, dynamics, autophagy (mitophagy). Mitochondrial dysfunction critically implicated Parkinson’s disease (PD), a brain disorder characterized by the progressive loss dopaminergic neurons substantia nigra. Consequently, impaired may play key role PD pathology. This affirmed work indicating that genes such as PRKN PINK1, which participate multiple processes, harbor PD-associated mutations. Furthermore, complex-I-inhibiting toxins like MPTP rotenone are known to cause Parkinson-like symptoms. At heart alpha-synuclein (αS), small synaptic protein misfolds aggregates form disease’s hallmark Lewy bodies. specific mechanisms through aggregated αS exerts its neurotoxicity still unknown; however, given vital both PD, an understanding how influences be elucidating pathogenesis discovering future therapeutic targets. Here, current knowledge relationship between reviewed, highlighting recent findings regarding effects on autophagy.

Язык: Английский

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A review on oxidative stress in organophosphate-induced neurotoxicity

The International Journal of Biochemistry & Cell Biology, Год журнала: 2025, Номер unknown, С. 106735 - 106735

Опубликована: Янв. 1, 2025

Язык: Английский

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Neuroprotective efficacy of berberine and caffeine against rotenone‐induced neuroinflammatory and oxidative disturbances associated with Parkinson’s disease via inhibiting α-synuclein aggregation and boosting dopamine release

Inflammopharmacology, Год журнала: 2025, Номер unknown

Опубликована: Март 9, 2025

Abstract Parkinson's disease (PD) is characterized by motor impairment, glial-mediated inflammation, redox imbalance, and α-synuclein (α-syn) aggregation. Conventional therapies relieve early PD symptoms, but they do not repair dopaminergic neurons. Berberine (BBR) caffeine (CAF), both natural alkaloids, exhibited neuroprotective effects in many neurodegenerative disorders. Consequently, we hypothesized that the combination of BBR CAF would offer protection against PD-related impairments rotenone (ROT)-induced rat model when compared to commercial drug, metformin (MTF). Our results showed combined administration (25 mg/kg/day) (2.5 for four weeks prevented deficits, weight reduction, dopamine (DA) depletion, monoamine oxidase (MAO) activity ROT-induced rats comparison with monotherapy along MTF. This produced a notable effect reducing tumor necrosis factor (TNF)-α interleukin-16 (IL-6) midbrain rats. combinations markedly normalized tyrosine hydroxylase (TH) levels decreased total α-syn α-syn-p ser129 aggregation increased protein phosphatase 2A (PP2A) levels. Histological analysis indicated damaged neurons significant amelioration co-administration CAF. The molecular docking had binding affinity pocket surrounding α-syn, PP2A, TH They are predicted serve as effective inhibitors enzyme-mediated phosphorylation α-syn- pser129 . Conclusively, presents novel strategy neuroprotection blocking initial events incidence, demonstrating considerable anti-oxidative anti-inflammatory benefits relative Graphical abstract

Язык: Английский

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Dabigatran Combined With Benztropine Ameliorates Cobalt Chloride-Induced Parkinsonism in Rats, Restores Protease-Activated Receptor 1 (PAR1), and Mitigates Oxidative Stress

Cureus, Год журнала: 2025, Номер unknown

Опубликована: Март 12, 2025

The presumed implication of thromboembolic and oxidative stress pathways in parkinsonism guided the current research toward exploration anticoagulant dabigatran etexilate (DE) as a thrombin inhibitor cobalt chloride (CoCl2)-induced (CIP) model, model significance to industrial toxins-related health issues. Oral CoCl2 (12.5 mg/kg) was administered daily for 60 days, with introduction benztropine mesylate (BM) (10 and/or DE (3 on day 31. Rearing, postural instability, pasta handling were evaluated, followed by histopathologic examination substantia nigra (SN) striatum (STR). expressions brain dopamine receptor 2 (D2 ), adenosine 1 (A1) 2A (A2A), protease-activated (PAR1), well levels (DA), endothelin (ET1), malondialdehyde (MDA), glutathione (GSH), assessed. BM+DE restored number rears control level, compared being reduced CIP model. first, second, third, average displacement distances superior either BM or restoring time finish eating adjustments forepaws while after affected DA level D2 level. A1 A2A , increasing A1/A2A beyond PAR1 ET1 levels. MDA both GSH exhibited highest percentage preserved neurons SN, which negatively correlated MDA. offers therapeutic potential triggered chronic exposure CoCl2. thrombin-related factors modulation dopaminergic-adenosinergic crosstalk is plausible.

Язык: Английский

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Target oxidative stress-induced disulfidptosis: novel therapeutic avenues in Parkinson’s disease

Molecular Brain, Год журнала: 2025, Номер 18(1)

Опубликована: Апрель 4, 2025

Abstract Background Parkinson’s disease (PD), a globally prevalent neurodegenerative disorder, has been implicated with oxidative stress (OS) as central pathomechanism. Excessive reactive oxygen species (ROS) trigger neuronal damage and may induce disulfidptosis—a novel cell death modality not yet characterized in PD pathogenesis. Method Integrated bioinformatics analyses were conducted using GEO datasets to identify PD-associated differentially expressed genes (DEGs). These subjected to: immune infiltration analysis, gene set enrichment analysis (GSEA), weighted co-expression network (WGCNA), intersection of stress-related (ORGs) disulfidptosis-related (DRGs) for functional annotation. Following hub identification, diagnostic performance was validated independent cohorts. LASSO regression applied feature selection, subsequent experimental validation MPTP-induced mouse models. Single-cell transcriptomic profiling molecular docking studies performed map target expression assess drug-target interactions. Result A total 1615 DEGs 200 WGCNA obtained, the ORGs DRGs resulted 202 DEORGs, 11 DEDRGs, 5 DED-ORGs (NDUFS2, LRPPRC, NDUFS1, GLUD1, MYH6). are mainly associated stress, respiratory electron transport chain, ATP metabolic process, phosphorylation, mitochondrial respiration, TCA cycle. 10 have good value, including dataset (AUC ≥ 0.507). yielded 6 genes, ACO2, CYCS, HSPA9, SNCA, SDHA, VDAC1. In mice model, SDHA decreased while VDAC1 increased, decreased. Additionally, it discovered that N-Acetylcysteine (NAC) could inhibit occurrence disulfidptosis model. Subsequently, distribution AUC > 0.7 different types brain analyzed. Finally, between anti-PD drugs entering clinical phase IV genes. LRPPRC low binding energy strong affinity duloxetine donepezil, energies -7.6 kcal/mol − 8.7 kcal/mol, respectively. Conclusion This study elucidates pathogenic role OS-induced progression. By identifying biomarkers (e.g., DED-ORGs) therapeutic targets LRPPRC), our findings provide mechanistic framework management lay groundwork future development.

Язык: Английский

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Parkinson’s Disease: The Neurodegenerative Enigma Under the “Undercurrent” of Endoplasmic Reticulum Stress

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(7), С. 3367 - 3367

Опубликована: Апрель 3, 2025

Parkinson's disease (PD), a prevalent neurodegenerative disorder, demonstrates the critical involvement of endoplasmic reticulum stress (ERS) in its pathogenesis. This review comprehensively examines role and molecular mechanisms ERS PD. represents cellular response triggered by imbalances (ER) homeostasis, induced factors such as hypoxia misfolded protein aggregation, which activate unfolded (UPR) through inositol-requiring enzyme 1 (IRE1), kinase R-like (PERK), activating transcription factor 6 (ATF6) pathways. Clinical, animal model, studies have consistently demonstrated strong association between PD ERS. Abnormal expression ERS-related molecules patients' brains cerebrospinal fluid (CSF) correlates with progression. In models (e.g., Drosophila mice), inhibition alleviates dopaminergic neuronal damage. Cellular experiments reveal that PD-mimicking pathological conditions induce ERS, while interactions mitochondrial dysfunction promote apoptosis. Mechanistically, (1) aggregation α-synuclein (α-syn) mutually reinforce neuron damage; (2) leucine-rich repeat 2 (LRRK2) gene mutations thrombospondin-1 (THBS1)/transforming growth beta (TGF-β1) interactions; (3) Parkin PTEN-induced (PINK1) regulate Furthermore, interacts dysfunction, oxidative stress, neuroinflammation to exacerbate injury. Emerging therapeutic strategies show significant potential, including artificial intelligence (AI)-assisted drug design targeting pathways precision medicine approaches exploring non-pharmacological interventions personalized electroacupuncture. Future research should focus on elucidating identifying novel targets develop more effective treatments for patients, ultimately improving their quality life.

Язык: Английский

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α -Lipoic acid alleviates Parkinson’s disease by suppressing S100A9-mediated pyroptosis

International Immunopharmacology, Год журнала: 2025, Номер 155, С. 114539 - 114539

Опубликована: Апрель 14, 2025

Язык: Английский

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Parkinson's disease and gut microbiota metabolites: The dual impact of vitamins and functional amyloids

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Год журнала: 2025, Номер 1871(6), С. 167862 - 167862

Опубликована: Апрель 18, 2025

Язык: Английский

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Volatile oil of Acori tatarinowii rhizoma: potential candidate drugs for mitigating dementia

Frontiers in Pharmacology, Год журнала: 2025, Номер 16

Опубликована: Апрель 23, 2025

Objective This study aims to elucidate the mitigating effects of volatile oil Acori tatarinowii rhizoma (ATR) on dementia, in order provide a reference for future research and applications ATR field dementia. Materials methods A search strategy was developed using terms such as “Acori rhizoma,” “Acorus Schott,” “Asarone,” “Dementia.” The literature conducted PubMed, Web Science, Google Scholar, studies not meeting inclusion criteria were excluded. summarizes main metabolites, active ingredients, toxicological properties, pharmacokinetic characteristics from with particular focus its potential mechanisms action. Furthermore, highlights limitations existing offers insights into directions. Results mitigates dementia through multiple pathways, including reducing abnormal protein aggregation, promoting neurogenesis, inhibiting neuronal apoptosis, regulating neurotransmitters, improving synaptic function, modulating autophagy, countering cellular stress, neuroinflammation, alleviating vascular risk factors. Conclusion multi-pathway pharmacological are well-aligned complex progression, highlighting significant therapeutic anti-dementia applications. provides new perspectives development more effective drugs. Nonetheless, further rigorous high-quality preclinical clinical investigations required address key issues, chemical characterization ATR, synergistic among toxicity profiles, definitive efficacy.

Язык: Английский

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