Cell-penetrant SELENOT mimetic protects dopaminergic neurons and ameliorates motor function
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ABSTRACT:
PROVIDER: PRJNA637314 | ENA |
REPOSITORIES: ENA
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Project description:Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor dysfunction for which there is an unmet need for better treatment options. Although oxidative stress is a common feature of neurodegenerative diseases, notably PD, there is currently no efficient therapeutic strategy able to tackle this system-wide pathophysiological process. Based on our previous observations of the potent antioxidant and neuroprotective activity of SELENOT, a vital thioredoxin-like selenoprotein, we designed the small peptide PSELT from its redox active site in order to determine its potential polyfunctional activity in PD models. PSELT proved to site in order to be protective for neurotoxin-treated dopaminergic neurons and fibers against oxidative stress determine its potential polyfunctional activity in PD models. PSELT proved to be protective for neurotoxin-treated dopaminergic neurons and fibers against oxidative stress and cell death. We demonstrate that PSELT is cell-permeable and acts in different subcellular compartments of dopaminergic neurons where oxidative stress exerts its deleterious effects. This protective activity prevented neurodegeneration and restored phosphorylated tyrosine hydroxylase levels, leading to improved motor skills in rodent models of PD
2021-02-08 | GSE151808 | GEO
Project description:Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms(1). Platelet factor 4 (PF4) is a platelets-secreted chemokine that can be activated by physical exercise. Recent studies showed that PF4 could improve cognition in aged mice(2), though whether it influences other neurological functions is vague. Here we investigated the role of PF4 in PD and normal aging mice. Intravenous administration of exogenous PF4 ameliorated both motor and non-motor symptoms of MPTP-induced PD mice, accompanying with reduced loss of nigrostriatal dopaminergic neurons and attenuated neuroinflammation in these regions. RNA sequencing showed that pathways related to inflammation were suppressed by PF4, which were confirmed by qPCR and immunohistochemical analysis. More interestingly, PF4 can also ameliorate the motor and non-motor symptoms after the loss of nigrostriatal dopaminergic neurons, and the efficacy can last for 3 weeks after PF4 administration. In addition, an improvement of motor performance and mood by PF4 was also observed in aged but not young mice. Collectively, our results show the potential of PF4 that not only be a therapeutic candidate for PD patients, but also be an option for aged people to improve their neurological performance.
2024-10-28 | GSE280106 | GEO
Project description:Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor dysfunction for which there is an unmet need for better treatment options. Although oxidative stress is a common feature of neurodegenerative diseases, notably PD, there is currently no efficient therapeutic strategy able to tackle this multi-target pathophysiological process. Based on our previous observations of the potent antioxidant and neuroprotective activity of SELENOT, a vital thioredoxin-like selenoprotein, we designed the small peptide PSELT from its redox active site to evaluate its antioxidant properties in vivo, and its potential polyfunctional activity in PD models. PSELT protects neurotoxin-treated dopaminergic neurons against oxidative stress and cell death, and their fibers against neurotoxic degeneration. PSELT is cell-permeable and acts in multiple subcellular compartments of dopaminergic neurons that are vulnerable to oxidative stress. In rodent models of PD, this protective activity prevented neurodegeneration, restored phosphorylated tyrosine hydroxylase levels, and led to improved motor skills. Transcriptomic analysis revealed that gene regulation by PSELT after MPP+ treatment negatively correlates with that occurring in PD, and positively correlates with that occurring after resveratrol treatment. Mechanistically, a major impact of PSELT is via nuclear stimulation of the transcription factor EZH2, leading to neuroprotection. Overall, these findings demonstrate the potential of PSELT as a therapeutic candidate for treatment of PD, targeting oxidative stress at multiple intracellular levels.
| S-EPMC7823055 | biostudies-literature
Project description:The cardinal motor symptoms of Parkinson´s disease (PD) are caused by the degeneration of dopaminergic neurons, making it in principle amenable to treatment by cell replacement therapy. Although this strategy has shown promise in animal models, it has not been as successful in clinical trials. One likely reason for this lack of success is the poor survival of grafted neurons. In animal models, glial cell line-derived neurotrophic factor (GDNF) increases the survival of transplanted dopaminergic neurons, but the ability of GDNF to promote survival is undoubtedly limited by its diffusion away from the graft site and its degradation. We report here on supramolecular nanofibers that display a GDNF-mimetic peptide on their surfaces. This nanostructure mimicked the biological effects of GDNF on human dopaminergic neurons by improving cell survival and promoting morphological, synaptic and electrophysiological maturation, as well as a neuroprotective effect that correlates with the upregulation of genes related to these biological processes. The GDNF nanostructures also enhanced the morphological maturation of human midbrain-like organoids. Thus, the GDNF supramolecular mimic provides a self-assembling matrix that could be delivered in the future with transplanted dopaminergic neurons to enhance their survival and maturation in vivo.
2024-07-01 | GSE253788 | GEO
Project description:Platelet factor 4 ameliorates motor and mood deficits in Parkinson’s disease
| PRJNA1176471 | ENA
Project description:We designed and demonstrated a synthetic strategy to derive mimetic Vγ9Vδ2 T cells endowed with NKRs from iPSCs. We used microarrays to compare mRNA expression profiles of such iPSC-derived mimetic Vγ9Vδ2 T cells with other peripheral blood lymphocytes.
2019-05-31 | GSE126035 | GEO
Project description:Pericyte-derived extracellular vesicle-mimetic nanovesicles ameliorates erectile dysfunction through Lipocalin 2 in the diabetic mice
| PRJNA759633 | ENA
Project description:Parkinson's disease (PD) is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SN) and accumulation of intracellular α-synuclein aggregates known as Lewy bodies and Lewy neurites. Levels of polyunsaturated fatty acids (PUFAs) are reduced in the SN of PD patients and G protein-coupled receptor 40 (GPR40) serves as a receptor for PUFAs, playing a role in neurodevelopment and neurogenesis. Additionally, GPR40 is implicated in neuropathological conditions such as apoptosis and inflammation, suggesting its potential as a therapeutic target in PD. In this study, we investigated the neuroprotective effects of the GPR40 agonist, TUG469, in PD models. Our results demonstrate that TUG469 reduces neurotoxicity induced by 6-OHDA in SH-SY5Y cells. In the 6-OHDA-induced PD model, TUG469 treatment improved motor impairment, preserved dopaminergic fibers and cell bodies in the striatum (ST) or SN, and attenuated 6-OHDA-induced microgliosis and astrogliosis in the brain. Furthermore, in a PD model involving the injection of mouse ɑ-syn fibrils into the brain (mPFFs-PD model), TUG469 treatment reduced the level of phosphorylated Ser129 ɑ-synuclein and decreased microgliosis and astrogliosis in mPFFs-PD model. Our investigation also revealed that TUG469 modulates inflammasome activation, apoptosis, and autophagy in the 6-OHDA-PD model, as evidenced by RNA-seq analysis and western blotting. In summary, our findings highlight the neuroprotective effects of GPR40 agonist on dopaminergic neurons and their potential as therapeutic agents for PD. These results underscore the importance of targeting GPR40 in PD treatment, particularly in mitigating neuroinflammation and preserving neuronal integrity.
2024-08-23 | GSE275257 | GEO
Project description:Pontocerebellar Hypoplasia Type 10 (PCH10) is a childhood neurodegenerative disease caused by bi-allelic p.R140H variants in CLP1, a multifunctional RNA kinase, by unknown pathophysiological mechanisms. Here, we combine novel patient data with mutation-specific in vivo and in vitro models to define motor neuron dysfunction as a penetrant, prominent feature of PCH10 and uncover a previously unrecognized mRNA misprocessing signature in motor neurons that likely contributes to pathology.
2021-11-01 | GSE183871 | GEO
Project description:Pontocerebellar Hypoplasia Type 10 (PCH10) is a childhood neurodegenerative disease caused by bi-allelic p.R140H variants in CLP1, a multifunctional RNA kinase, by unknown pathophysiological mechanisms. Here, we combine novel patient data with mutation-specific in vivo and in vitro models to define motor neuron dysfunction as a penetrant, prominent feature of PCH10 and uncover a previously unrecognized mRNA misprocessing signature in motor neurons that likely contributes to pathology.
2021-11-01 | GSE183869 | GEO