ERK1/2-dependent TSPO overactivation associates with the loss of mitophagy and mitochondrial respiration in ALS

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(2)

Published: Feb. 15, 2023

Abstract Mitochondrial dysfunction and the loss of mitophagy, aimed at recycling irreversibly damaged organelles, contribute to onset amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease affecting spinal cord motor neurons. In this work, we showed that reduction mitochondrial respiration, exactly oxygen flows linked ATP production maximal capacity, correlates with appearance most common ALS symptoms in transgenic mouse model expressing SOD1 G93A mutant. This is result equal inhibition respiration complex I II electron transport chain, but not their protein levels. Since overall mass was unvaried, investigated expression Translocator Protein (TSPO), small whose overexpression recently mitophagy Parkinson’s disease. Here clearly levels TSPO are significantly increased mice. Mechanistically, increase overactivation ERK1/2 pathway decrease mitophagy-related marker Atg12, indicating occurrence impairments activation mitophagy. Overall, our work sets out as key regulator homeostasis ALS.

Language: Английский

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Synaptic plasticity and neuroprotection: The molecular impact of flavonoids on neurodegenerative disease progression

Neuroscience, Journal Year: 2025, Volume and Issue: 569, P. 161 - 183

Published: Feb. 7, 2025

Language: Английский

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Unlocking the therapeutic potential of protein kinase inhibitors in neurodegenerative and psychiatric disorders

Published: Feb. 26, 2025

Protein phosphorylation is a fundamental regulatory mechanism governing broad spectrum of cellular processes. In the nervous system, it critical for modulating neurotransmitter release, synaptic plasticity, neuronal excitability, and cell survival. Dysregulation protein kinase activity closely linked to pathogenesis various neurological psychiatric disorders, positioning several kinases as promising therapeutic targets. Although inhibitors (PKIs), major class compounds that modulate activity, have shown considerable success in oncology, their application diseases remains early stages exploration. Of 82 PKIs approved by Food Drug Administration (FDA), 37 are now preclinical clinical trials conditions, primarily targeting signaling pathways mediated key implicated these diseases. This review examines roles effects neurodegenerative, psychiatric, selected such autism disorders (ASD) epilepsy. We focus on Abelson I (ABL1), calmodulin-dependent II (CaMKII), casein 1δ (CK1δ), c-Jun N-terminal (JNK), cyclin-dependent 5 (CDK5), dual-specificity tyrosine-phosphorylated regulated 1A (DYRK1A), leucine-rich repeat 2 (LRRK2), extracellular signal-regulated 1/2 (ERK1/2), glycogen synthase 3β (GSK3β), mammalian target rapamycin (mTOR), p38 mitogen-activated kinase, C (PKC) neurodegenerative Additionally, we discuss CaMKII, CDK5, ERK1/2, PI3K/AKT/GSK3, A (PKA), PKC focusing schizophrenia mood analyze GSK3β, mTOR ASD underscores potential while highlighting ongoing challenges need further research refine kinase-targeted therapies.

Language: Английский

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Guggulsterone Selectively Modulates STAT-3, mTOR, and PPAR-Gamma Signaling in a Methylmercury-Exposed Experimental Neurotoxicity: Evidence from CSF, Blood Plasma, and Brain Samples

Molecular Neurobiology, Journal Year: 2024, Volume and Issue: 61(8), P. 5161 - 5193

Published: Jan. 3, 2024

Language: Английский

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Effect of alpha-mangostin in the prevention of behavioural and neurochemical defects in methylmercury-induced neurotoxicity in experimental rats

Toxicology Reports, Journal Year: 2022, Volume and Issue: 9, P. 977 - 998

Published: Jan. 1, 2022

Methylmercury (MeHg+) is a known neurotoxin that causes progressive motor neuron degeneration in the central nervous system. Axonal degeneration, oligodendrocyte and myelin basic protein (MBP) deficits are among neuropathological abnormalities caused by MeHg+ amyotrophic lateral sclerosis (ALS). This results demyelination death both humans animals. Previous experimental studies have confirmed overexpression of extracellular signalling regulated kinase (ERK1/2) contributes to glutamate excitotoxicity, inflammatory response microglial cells, (OL) dysfunction promotes loss. Alpha-mangostin (AMG), an active ingredient obtained from tree "Garcinia mangostana Linn," has been used animals treat variety brain disorders, including Parkinson's Huntington's disease memory impairment, Alzheimer's disease, schizophrenia, schizophrenia. AMG traditionally as antioxidant, anti-inflammatory, neuroprotective agent.Accordingly, we investigated therapeutic potential (100 200 mg/kg) rats with methylmercury (MeHg+)-induced neurotoxicity. The effect on behavioural, cellular, molecular, other gross pathological changes, such histopathological alterations -treated rat brains, presented. neurological behaviour was evaluated using Morris water maze (MWM), open field test (OFT), grip strength (GST), force swim (FST). In addition, investigate AMG's restoring MBP levels cerebral spinal fluid whole homogenate. apoptotic, pro-inflammatory, oxidative stress markers were measured blood plasma samples According findings this study, decreases ERK-1/2 modulates neurochemical minimising -induced

Language: Английский

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Carbon dioxide and MAPK signalling: towards therapy for inflammation

Cell Communication and Signaling, Journal Year: 2023, Volume and Issue: 21(1)

Published: Oct. 10, 2023

Abstract Inflammation, although necessary to fight infections, becomes a threat when it exceeds the capability of immune system control it. In addition, inflammation is cause and/or symptom many different disorders, including metabolic, neurodegenerative, autoimmune and cardiovascular diseases. Comorbidities advanced age are typical predictors more severe cases seasonal viral infection, with COVID-19 clear example. The primary importance mitogen-activated protein kinases (MAPKs) in course evident mechanisms by which cells infected SARS-CoV-2; cytokine storm that profoundly worsens patient’s condition; pathogenesis diseases, such as diabetes, obesity, hypertension, contribute worsened prognosis; post-COVID-19 complications, brain fog thrombosis. An increasing number reports have revealed MAPKs regulated carbon dioxide (CO 2 ); hence, we reviewed literature identify associations between CO possible therapeutic benefits resulting from elevation levels. regulates key processes leading inflammation, effects (or bicarbonate, HCO 3 − ) been documented all abovementioned comorbidities complications play roles. overlapping MAPK signalling pathways contexts allergy, apoptosis cell survival, pulmonary oedema (alveolar fluid resorption), mechanical ventilation–induced responses lungs related mitochondria also discussed.

Language: Английский

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Cdk5 and aberrant cell cycle activation at the core of neurodegeneration

Neural Regeneration Research, Journal Year: 2022, Volume and Issue: 18(6), P. 1186 - 1186

Published: Nov. 26, 2022

Neurodegenerative diseases are caused by the progressive loss of specific neurons. The exact mechanisms action these unknown, and many studies have focused on pathways related to abnormal accumulation processing proteins, mitochondrial dysfunction, oxidative stress leading apoptotic death. However, a growing body evidence indicates that aberrant cell cycle re-entry plays major role in pathogenesis neurodegeneration. activation mature neurons could be promoted several signaling mechanisms, including c-Jun N-terminal kinases, p38 mitogen-activated protein kinase/extracellular signal-regulated kinase cascades; post-translational modifications such as Tau-phosphorylation; DNA damage response. In all events, implicated Cdk5, proline-directed serine/threonine kinase, seems responsible for cellular processes axon growth, neurotransmission, synaptic plasticity, neuronal migration, maintenance survival. under pathological conditions, Cdk5 dysregulation may lead post-mitotic Thus, hyperactivation, its physiologic activator p25, hyper-phosphorylates downstream substrates neurodegenerative diseases. This review summarizes factors stress, response, pathway disturbance, Ubiquitin proteasome malfunction contributing It also describes how linked greater or lesser extent with Cdk5. it offers global vision function cycle-related proteins focus this contributes development Alzheimer's disease, Parkinson's amyotrophic lateral sclerosis, Huntington's disease activation.

Language: Английский

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Melanoma cells induce dedifferentiation and metabolic changes in adipocytes present in the tumor niche

Cellular & Molecular Biology Letters, Journal Year: 2023, Volume and Issue: 28(1)

Published: July 22, 2023

Abstract Background One of the factors that affect progression melanoma is tumor microenvironment, which consists cellular elements, extracellular matrix, acidification, and a hypoxic state. Adipocytes are one types cell present in niche localized deepest layer skin. However, relationship between fat cells remains unclear. Methods We assessed influence on adipocytes using an indirect coculture system. estimated level cancer-associated adipocyte (CAA) markers through quantitative PCR analysis. The fibroblastic phenotype CAAs was confirmed by staining western blotting lipid content detection LipidSpot analysis Oil Red O. expression proteins involved synthesis, delipidation, metabolic processes were or Lactate secretion established Lactate-Glo™ assay. Proteins secreted identified cytokine angiogenesis arrays. proliferation cocultured with XTT Statistical performed one-way ANOVA followed Tukey’s test GraphPad Prism 7 software. Results Obtained decreased levels leptin, adiponectin, resistin, FABP4. presented features, such as similar proteolytic pattern to 3T3L1 fibroblasts increased vimentin TGFβRIII. Melanoma led reduction CAAs, possibly downregulation synthesis pathways (lower FADS, SC4MOL, FASN) enhancement lipolysis (higher phosphorylation ERK STAT3). higher IL6 SerpinE1 produced less CCL2, CXCL1, angiogenic molecules. also showed changes comprising lactate enhanced production glucose, lactate, ion transporters. In addition, observed following resulted rate cancer cells. Conclusions adipocytes, might be related delipidation synthesis. Fibroblast-like may reason for accelerated

Language: Английский

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CK1δ/ε kinases regulate TDP-43 phosphorylation and are therapeutic targets for ALS-related TDP-43 hyperphosphorylation

Neurobiology of Disease, Journal Year: 2024, Volume and Issue: 196, P. 106516 - 106516

Published: April 25, 2024

Hyperphosphorylated TAR DNA-binding protein 43 (TDP-43) aggregates in the cytoplasm of neurons is neuropathological hallmark amyotrophic lateral sclerosis (ALS) and a group neurodegenerative diseases collectively referred to as TDP-43 proteinopathies that includes frontotemporal dementia, Alzheimer's disease, limbic onset age-related encephalopathy. The mechanism phosphorylation poorly understood. Previously we reported casein kinase 1 epsilon gene (CSNK1E encoding CK1ε protein) being tightly correlated with phosphorylated (pTDP-43) pathology. Here pursued studies investigate cellular models vitro how CK1δ (a closely related family sub-member) mediate disease. We first validated binding interaction between either using activity assays predictive bioinformatic database. utilized novel inducible generated translocated cytoplasmic aggregation. Reducing CK1 siRNA or small molecule chemical inhibitors resulted significant reduction pTDP-43, both soluble insoluble fractions. also established are primary kinases phosphorylate compared CK2α, CDC7, ERK1/2, p38α/MAPK14, TTBK1, other identified have been implicated phosphorylation. Throughout our studies, were careful examine fractions, critical fractions aggregation diseases. These results identify CK1s involved hyperphosphorylation vitro, turn potential therapeutic targets by way CK1δ/ε inhibitors.

Language: Английский

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Disruptions in cellular communication: Molecular interplay between glutamate/NMDA signalling and MAPK pathways in neurological disorders

Neuroscience, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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