Tau phosphorylation suppresses oxidative stress-induced mitophagy via FKBP8 receptor modulation

PLoS ONE, Год журнала: 2025, Номер 20(1), С. e0307358 - e0307358

Опубликована: Янв. 3, 2025

Neurodegenerative diseases are often characterized by mitochondrial dysfunction. In Alzheimer’s disease, abnormal tau phosphorylation disrupts mitophagy, a quality control process through which damaged organelles selectively removed from the network. The precise mechanism this occurs remains unclear. Previously, we showed that has been mutated at Thr-231 to glutamic acid mimic an Alzheimer’s-relevant phospho-epitope expressed early in disease inhibits oxidative stress-induced mitophagy Caenorhabditis elegans . Here, use immortalized mouse hippocampal neuronal cell lines extend result into mammalian cells. Specifically, show phosphomimetic Ser-396/404 (EC) or Thr-231/Ser-235 (EM) partly induction paraquat, potent inducer of stress. Moreover, combination immunologic and biochemical approaches demonstrates levels receptor FKBP8, significantly decrease response paraquat cells expressing EC EM mutants, but not wildtype tau. contrast, treatment results receptors FUNDC1 BNIP3 presence both mutants. Interestingly, FKBP8 is normally trafficked endoplasmic reticulum during stress induced our support model where trafficking impacted disease-relevant tau, perhaps direct interaction. We provide new insights molecular mechanisms underlying pathology highlight as potential target for mitigating dysfunction neurodegenerative diseases.

Язык: Английский

---

Monoamine Oxidase Inhibitors in Toxic Models of Parkinsonism

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(3), С. 1248 - 1248

Опубликована: Янв. 31, 2025

Monoamine oxidase inhibitors are widely used for the symptomatic treatment of Parkinson's disease (PD). They demonstrate antiparkinsonian activity in different toxin-based models induced by 6-hydroxydopamine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and pesticides (rotenone paraquat). In some models, such as MPTP-induced PD, MAO prevent formation neurotoxin MPP+ from protoxin MPTP. Regardless toxin's nature, potent dopamine loss reduction, hydrogen peroxide, peroxide signaling, accumulation peroxide-derived reactive oxygen species responsible development oxidative stress. It becomes increasingly clear that metabolites (e.g., rasagiline metabolite 1-R-aminoindan) possess their own bio-pharmacological activities unrelated to parent compound. addition, various exhibit multitarget action, which MAO-independent effects prevail. This opens new prospects novel therapeutics based on simultaneous actions several prospective targets therapy PD.

Язык: Английский

---

Fucoxanthinol Mitigates the Cytotoxic Effect of Chlorpyrifos and MPTP on the Dopaminergic Differentiation of SH-SY5Y Human Neuroblastoma Cells

Journal of Molecular Neuroscience, Год журнала: 2025, Номер 75(2)

Опубликована: Апрель 8, 2025

Abstract This study investigates the neuroprotective effects of fucoxanthinol (FXL) against toxic activities two compounds known to induce neurotoxic in humans and animals. MPTP (1-methyl- 4-phenyl- 1,2,3,6-tetrahydropyridine) induces Parkinson’s disease (PD)-like phenotypes by inhibiting mitochondrial complex I dopaminergic neurons. Chlorpyrifos (CPF), another agent, is associated with acute long-term neurotoxicity primarily through acetylcholinesterase (AChE) inhibition. FXL demonstrated ability reverse CPF SH-SY5Y neuronal cell models. Treatment enhances function cells exposed MPTP, as increased levels Adenosine triphosphate (ATP), membrane potential (MMP), complexes activities, oxygen consumption rates, pyruvate dehydrogenase (PDH) mitophagy pathways. improvement highlights FXL’s counteract dysfunction induced these agents. Additionally, reduces oxidative damage viability. At molecular level, were also modulation apoptotic markers, including Bcl- 2 markers. Molecular docking data further support outcomes our vitro studies. Multivariable analysis FXL. These findings indicate mitigate CPF- MPTP-induced neurotoxicity, suggesting its promise a therapeutic agent for managing observe PD.

Язык: Английский

---

An In Silico and In Vitro Assessment of the Neurotoxicity of Mefloquine

Biomedicines, Год журнала: 2024, Номер 12(3), С. 505 - 505

Опубликована: Фев. 23, 2024

Mefloquine (MQ) is a quinoline-based anti-malarial drug used for chemoprophylaxis or as treatment in combination with artesunate. Although MQ has clear anti-Plasmodium falciparum properties, it can induce neurotoxicity and undesired neuropsychiatric side effects humans. Hence, this study aimed to characterize the of using human neuroblastoma SH-SY5Y cells. The on neuronal toxicity cell viability were investigated over concentration range 1–100 µM 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) lactate dehydrogenase (LDH) assays. influence cellular bioenergetics was examined by measuring ATP levels from induction reactive oxygen species (ROS). An silico approach assess potential mediated via binding active sites acetylcholinesterase (AChE) butyrylcholinesterase (BuChE) then experimentally validated vitro enzymatic cytotoxic cells exposure duration dependent manner induced significant reduction at concentrations ≥25 after 24 h exposure. adversely impacted significantly depleted production ≥1 h. MQ-induced ROS production, which correlated apoptosis, revealed flow cytometry. In studies suggested that dual cholinesterase inhibitor one remarkably potent BuChE. Modelling data supported showed inhibited both AChE BuChE enzymes. summary, an antimalarial may impacting perturbing activity cholinesterases relevant dosage.

Язык: Английский

---

Alcohol Triggers the Accumulation of Oxidatively Damaged Proteins in Neuronal Cells and Tissues

Antioxidants, Год журнала: 2024, Номер 13(5), С. 580 - 580

Опубликована: Май 8, 2024

Alcohol is toxic to neurons and can trigger alcohol-related brain damage, neuronal loss, cognitive decline. Neuronal cells may be vulnerable alcohol toxicity damage from oxidative stress after differentiation. To consider this further, the of undifferentiated SH-SY5Y was compared with that had been acutely differentiated. Cells were exposed over a concentration range 0–200 mM for up 24 h effects on cell viability evaluated via MTT LDH assays. Effects mitochondrial morphology examined transmission electron microscopy, functionality using measurements ATP production reactive oxygen species (ROS). reduced depleted levels in concentration- exposure duration-dependent manner, more toxicity. resulted neurite retraction, altered morphology, increased ROS proportion concentration; these peaked 3 6 exposures significantly higher differentiated cells. Protein carbonyl content (PCC) lagged behind 12 h, increasing concentration, Carbonylated proteins characterised by their denatured molecular weights overlapped those adult post-mortem tissue, PCC alcoholic subjects than matched controls. Hence, potentially tissue accumulation oxidatively damaged proteins.

Язык: Английский

---

Tau phosphorylation suppresses oxidative stress-induced mitophagy via FKBP8 receptor modulation

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 9, 2024

Abstract Neurodegenerative diseases are often characterized by mitochondrial dysfunction. In Alzheimer’s disease, abnormal tau phosphorylation disrupts mitophagy, a quality control process through which damaged organelles selectively removed from the network. The precise mechanism this occurs remains unclear. Previously, we showed that has been mutated at Thr-231 to glutamic acid mimic an Alzheimer’s-relevant phospho-epitope expressed early in disease inhibits oxidative stress-induced mitophagy C. elegans . Here, use immortalized mouse hippocampal neuronal cell lines extend result into mammalian cells. Specifically, show phosphomimetic Ser-396/404 (EC) or Thr-231/Ser-235 (EM) partly induction paraquat, potent inducer of stress. Moreover, combination immunologic and biochemical approaches demonstrates levels receptor FKBP8, significantly decrease response paraquat cells expressing EC EM mutants, but not wildtype tau. contrast, treatment results receptors FUNDC1 BNIP3 presence both mutants. Interestingly, FKBP8 is normally trafficked endoplasmic reticulum during stress induced our support model where trafficking impacted disease-relevant tau, perhaps direct interaction. We provide new insights molecular mechanisms underlying pathology highlight as potential target for mitigating dysfunction neurodegenerative diseases.

Язык: Английский

---

Exploring the Neuroprotective Potential of Desmodium Species: Insights into Radical Scavenging Capacity and Mechanisms against 6-OHDA-Induced Neurotoxicity

Plants, Год журнала: 2024, Номер 13(13), С. 1742 - 1742

Опубликована: Июнь 24, 2024

In this study, we collected seven prevalent Taiwanese Desmodium plants, including three species with synonymous characteristics, in order to assess their antioxidant phytoconstituents and radical scavenging capacities. Additionally, compared inhibitory activities on monoamine oxidase (MAO) 6-hydroxydopamine (6-OHDA) auto-oxidation. Subsequently, evaluated the neuroprotective potential of D. pulchellum 6-OHDA-induced nerve damage SH-SY5Y cells delved into underlying mechanisms. Among species, exhibited most robust ABTS capacity relative reducing power; correspondingly, it had highest total phenolic phenylpropanoid contents. Meanwhile, motorium showcased best hydrogen peroxide and, notably, sequax demonstrated remarkable prowess DPPH superoxide capacity, along selective activity against MAO-B. Of aforementioned emerged as frontrunner inhibiting 6-OHDA auto-oxidation conferring neuroprotection neuronal cells. Furthermore, effectively mitigated increase intracellular ROS MDA levels through restoring defense system. Therefore, suggest that possesses effects neurotoxicity due its ability restore activities.

Язык: Английский

---

Immortalized neuronal lines versus human induced pluripotent stem cell-derived neurons as in vitro toxicology models

Advances in neurotoxicology, Год журнала: 2024, Номер unknown, С. 47 - 81

Опубликована: Янв. 1, 2024

Язык: Английский

---