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Neurotherapeutics : the Journal of the... Oct 2020Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons associated with dysregulation of iron homeostasis in the...
Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons associated with dysregulation of iron homeostasis in the brain. Ferroptosis is an iron-dependent cell death process that serves as a significant regulatory mechanism in PD. However, its underlying mechanisms are not yet fully understood. By performing RNA sequencing analysis, we found that the main iron storage protein ferritin heavy chain 1 (FTH1) is differentially expressed in the rat 6-hydroyxdopamine (6-OHDA) model of PD compared with control rats. Our present work demonstrates that FTH1 is involved in iron accumulation and the ferroptosis pathway in this model. Knockdown of FTH1 in PC-12 cells significantly inhibited cell viability and caused mitochondrial dysfunction. Moreover, FTH1 was found to be involved in ferritinophagy, a selective form of autophagy involving the degradation of ferritin by ferroptosis. Overexpression of FTH1 in PC-12 cells impaired ferritinophagy and downregulated microtubule-associated protein light chain 3 and nuclear receptor coactivator 4 expression, ultimately suppressing cell death induced by ferroptosis. Consistent with these findings, the ferritinophagy inhibitors chloroquine and bafilomycin A1 inhibited ferritin degradation and ferroptosis in 6-OHDA-treated PC-12 cells. This entire process was mediated by the cyclic regulation of FTH1 and ferritinophagy. Taken together, these results suggest that FTH1 links ferritinophagy and ferroptosis in the 6-OHDA model of PD, and provide a new perspective and potential for a pharmacological target in this disease.
Topics: Animals; Cell Survival; Ferritins; Ferroptosis; Male; Oxidopamine; Oxidoreductases; PC12 Cells; Parkinsonian Disorders; Rats; Rats, Sprague-Dawley
PubMed: 32959272
DOI: 10.1007/s13311-020-00929-z -
Molecular Therapy : the Journal of the... Oct 2022Parkinson's disease is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra with no effective cure available....
Parkinson's disease is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra with no effective cure available. MicroRNA-124 has been regarded as a promising therapeutic entity for Parkinson's disease due to its pro-neurogenic and neuroprotective roles. However, its efficient delivery to the brain remains challenging. Here, we used umbilical cord blood mononuclear cell-derived extracellular vesicles as a biological vehicle to deliver microRNA (miR)-124-3p and evaluate its therapeutic effects in a mouse model of Parkinson's disease. In vitro, miR-124-3p-loaded small extracellular vesicles induced neuronal differentiation in subventricular zone neural stem cell cultures and protected N27 dopaminergic cells against 6-hydroxydopamine-induced toxicity. In vivo, intracerebroventricularly administered small extracellular vesicles were detected in the subventricular zone lining the lateral ventricles and in the striatum and substantia nigra, the brain regions most affected by the disease. Most importantly, although miR-124-3p-loaded small extracellular vesicles did not increase the number of new neurons in the 6-hydroxydopamine-lesioned striatum, the formulation protected dopaminergic neurons in the substantia nigra and striatal fibers, which fully counteracted motor behavior symptoms. Our findings reveal a novel promising therapeutic application of small extracellular vesicles as delivery agents for miR-124-3p in the context of Parkinson's disease.
Topics: Animals; Disease Models, Animal; Dopaminergic Neurons; Extracellular Vesicles; Mice; MicroRNAs; Neurodegenerative Diseases; Oxidopamine; Parkinson Disease; Substantia Nigra
PubMed: 35689381
DOI: 10.1016/j.ymthe.2022.06.003 -
Microbiome Jan 2021Parkinson's disease (PD) is a neurodegenerative disorder with no absolute cure. The evidence of the involvement of gut microbiota in PD pathogenesis suggests the need to...
BACKGROUND
Parkinson's disease (PD) is a neurodegenerative disorder with no absolute cure. The evidence of the involvement of gut microbiota in PD pathogenesis suggests the need to identify certain molecule(s) derived from the gut microbiota, which has the potential to manage PD. Osteocalcin (OCN), an osteoblast-secreted protein, has been shown to modulate brain function. Thus, it is of interest to investigate whether OCN could exert protective effect on PD and, if yes, whether the underlying mechanism lies in the subsequent changes in gut microbiota.
RESULTS
The intraperitoneal injection of OCN can effectively ameliorate the motor deficits and dopaminergic neuronal loss in a 6-hydroxydopamine-induced PD mouse model. The further antibiotics treatment and fecal microbiota transplantation experiments confirmed that the gut microbiota was required for OCN-induced protection in PD mice. OCN elevated Bacteroidetes and depleted Firmicutes phyla in the gut microbiota of PD mice with elevated potential of microbial propionate production and was confirmed by fecal propionate levels. Two months of orally administered propionate successfully rescued motor deficits and dopaminergic neuronal loss in PD mice. Furthermore, AR420626, the agonist of FFAR3, which is the receptor of propionate, mimicked the neuroprotective effects of propionate and the ablation of enteric neurons blocked the prevention of dopaminergic neuronal loss by propionate in PD mice.
CONCLUSIONS
Together, our results demonstrate that OCN ameliorates motor deficits and dopaminergic neuronal loss in PD mice, modulating gut microbiome and increasing propionate level might be an underlying mechanism responsible for the neuroprotective effects of OCN on PD, and the FFAR3, expressed in enteric nervous system, might be the main action site of propionate. Video abstract.
Topics: Animals; Anti-Bacterial Agents; Disease Models, Animal; Disease Progression; Dopaminergic Neurons; Fecal Microbiota Transplantation; Gastrointestinal Microbiome; Infusions, Parenteral; Male; Mice; Neuroprotective Agents; Osteocalcin; Oxidopamine; Parkinson Disease; Propionates; Receptors, G-Protein-Coupled
PubMed: 33517890
DOI: 10.1186/s40168-020-00988-6 -
Cells Jul 2022Parkinson's disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer's disease. The principal pathological feature of PD is the progressive...
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer's disease. The principal pathological feature of PD is the progressive loss of dopaminergic neurons in the ventral midbrain. This pathology involves several cellular alterations: oxidative stress, mitochondrial dysfunction, loss of proteostasis, and autophagy impairment. Moreover, in recent years, lipid metabolism alterations have become relevant in PD pathogeny. The modification of lipid metabolism has become a possible way to treat the disease. Because of this, we analyzed the effect and possible mechanism of action of linoleic acid (LA) on an SH-SY5Y PD cell line model and a PD mouse model, both induced by 6-hydroxydopamine (6-OHDA) treatment. The results show that LA acts as a potent neuroprotective and anti-inflammatory agent in these PD models. We also observed that LA stimulates the biogenesis of lipid droplets and improves the autophagy/lipophagy flux, which resulted in an antioxidant effect in the in vitro PD model. In summary, we confirmed the neuroprotective effect of LA in vitro and in vivo against PD. We also obtained some clues about the novel neuroprotective mechanism of LA against PD through the regulation of lipid droplet dynamics.
Topics: Animals; Autophagy; Cell Line, Tumor; Humans; Linoleic Acid; Lipid Droplets; Mice; Neuroblastoma; Neurodegenerative Diseases; Oxidopamine; Parkinson Disease
PubMed: 35892594
DOI: 10.3390/cells11152297 -
European Review For Medical and... Jul 2021Drugs affecting dopaminergic neurotransmission may exert toxic and beneficial effects that persist after discontinuation by modulating gene expression in key brain... (Review)
Review
OBJECTIVE
Drugs affecting dopaminergic neurotransmission may exert toxic and beneficial effects that persist after discontinuation by modulating gene expression in key brain regions. Drug addiction, cravings and the tardive symptoms associated with chronic exposure to antipsychotics are among the most common processes attributed to long-term dopaminergic neurotoxicity. The purpose of this review was to investigate the mechanisms of dopaminergic neurotoxicity induced by neuroleptic drugs, dopamine agonists, levodopa, stimulants and known dopaminergic neurotoxins MATERIALS AND METHODS: A PubMed search for each of the dopaminergic compounds in question was carried out. The heterogenous nature of the relevant preclinical studies precluded a systematic review, so a narrative review was carried out.
RESULTS
The dopaminergic neurotoxins 6-oxidopamine and 1-methyl-4-phenyl-tetrahydropyridine (MPTP) promote oxidative stress and inhibit mitochondrial function, while their affinity for the dopamine transporter ensures they are attain toxic intracellular concentrations exclusively in dopaminergic neurons. Stimulants which inhibit the vesicular monoamine transporter such as amphetamine and its derivatives promote oxidative stress by greatly increasing intracellular dopamine concentrations and enabling dopamine autooxidation. Antipsychotics increase dopamine release and turnover by blocking autoinhibitory D2 receptors and lead to upregulation of post-synaptic D2 receptors. Dopamine agonists may slow the progression of Parkinson's disease by reducing dopamine turnover, but downregulation of D2 receptors may underlie their behavioural toxicity.
CONCLUSIONS
Though the mechanisms have not been completely elucidated yet, it seems drugs which affect dopaminergic neurotransmission may exert long-term effects which reverse slowly upon discontinuation, if at all. Until the nature of these changes is clear it would be best to utilize drugs which affect dopaminergic neurotransmission cautiously especially if prolonged treatment is required.
Topics: Antipsychotic Agents; Dopamine; Dopaminergic Neurons; Humans; Levodopa; Methamphetamine; Mitochondria; Neurotoxicity Syndromes; Oxidation-Reduction; Oxidative Stress; Synaptic Transmission
PubMed: 34286493
DOI: 10.26355/eurrev_202107_26243 -
Neurotoxicity Research Feb 2020Salsolinol (6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydroisoquinoline), widely available in many edibles, is considered to alter the function of dopaminergic neurons in the...
Salsolinol (6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydroisoquinoline), widely available in many edibles, is considered to alter the function of dopaminergic neurons in the central nervous system and thus, multiple hypotheses on its either physiological and/or pathophysiological role have emerged. The aim of our work was to revisit its potentially neurotoxic and/or neuroprotective role through a series of both in vitro and in vivo experiments. Salsolinol in the concentration range 10-250 μM did not show any significant release of lactate dehydrogenase from necrotic SH-SY5Y cells and was able in the concentration of 50 and 100 μM to rescue SH-SY5Y cells from death induced by HO. Its neuroprotective effect against neurotoxin 6-hydroxydopamine was also determined. Salsolinol was found to decrease significantly the reactive oxygen species level in SH-SY5Y cells treated by 500 μM HO and the caspase activity induced by 300 μM of HO or 100 μM of 6-hydroxydopamine. Serum levels of TNFα and CRP of salsolinol-treated rats were not significantly different from control animals. Both TNFα and CRP served as indirect markers of neurotoxicity and/or neuroprotection. Although the neurotoxic properties of salsolinol have numerously been emphasized, its neuroprotective properties should not be neglected and need greater consideration.
Topics: Animals; Apoptosis; Cell Death; Cell Line, Tumor; Cells, Cultured; Dose-Response Relationship, Drug; Humans; Inflammation Mediators; Isoquinolines; Male; Neuroprotective Agents; Oxidopamine; Rats; Rats, Wistar
PubMed: 31732870
DOI: 10.1007/s12640-019-00118-7 -
ELife May 2022Lineage reprogramming of resident glial cells to dopaminergic neurons (DAns) is an attractive prospect of the cell-replacement therapy for Parkinson's disease (PD)....
Lineage reprogramming of resident glial cells to dopaminergic neurons (DAns) is an attractive prospect of the cell-replacement therapy for Parkinson's disease (PD). However, it is unclear whether repressing polypyrimidine tract binding protein 1 (PTBP1) could efficiently convert astrocyte to DAns in the substantia nigra and striatum. Although reporter-positive DAns were observed in both groups after delivering the adeno-associated virus (AAV) expressing a reporter with shRNA or CRISPR-CasRx to repress astroglial PTBP1, the possibility of AAV leaking into endogenous DAns could not be excluded without using a reliable lineage-tracing method. By adopting stringent lineage-tracing strategy, two other studies show that either knockdown or genetic deletion of quiescent astroglial PTBP1 fails to obtain induced DAns under physiological condition. However, the role of reactive astrocytes might be underestimated because upon brain injury, reactive astrocyte can acquire certain stem cell hallmarks that may facilitate the lineage conversion process. Therefore, whether reactive astrocytes could be genuinely converted to DAns after PTBP1 repression in a PD model needs further validation. In this study, we used -mediated specific astrocyte-lineage-tracing method to investigate whether reactive astrocytes could be converted to DAns in a 6-hydroxydopamine (6-OHDA) mouse model of PD. However, we found that no astrocyte-originated DAn was generated after effective and persistent knockdown of astroglial PTBP1 either in the substantia nigra or in striatum, while AAV 'leakage' to nearby neurons was easily observed. Our results confirm that repressing PTBP1 does not convert astrocytes to DAns, regardless of physiological or PD-related pathological conditions.
Topics: Animals; Astrocytes; Dependovirus; Disease Models, Animal; Dopaminergic Neurons; Heterogeneous-Nuclear Ribonucleoproteins; Mice; Oxidopamine; Parkinson Disease; Polypyrimidine Tract-Binding Protein; Substantia Nigra
PubMed: 35535997
DOI: 10.7554/eLife.75636 -
Proceedings of the National Academy of... Jul 2022Clinical evidence suggests that pain hypersensitivity develops in patients with attention-deficit/hyperactivity disorder (ADHD). However, the mechanisms and neural...
Clinical evidence suggests that pain hypersensitivity develops in patients with attention-deficit/hyperactivity disorder (ADHD). However, the mechanisms and neural circuits involved in these interactions remain unknown because of the paucity of studies in animal models. We previously validated a mouse model of ADHD obtained by neonatal 6-hydroxydopamine (6-OHDA) injection. Here, we have demonstrated that 6-OHDA mice exhibit a marked sensitization to thermal and mechanical stimuli, suggesting that phenotypes associated with ADHD include increased nociception. Moreover, sensitization to pathological inflammatory stimulus is amplified in 6-OHDA mice as compared to shams. In this ADHD model, spinal dorsal horn neuron hyperexcitability was observed. Furthermore, ADHD-related hyperactivity and anxiety, but not inattention and impulsivity, are worsened in persistent inflammatory conditions. By combining in vivo electrophysiology, optogenetics, and behavioral analyses, we demonstrated that anterior cingulate cortex (ACC) hyperactivity alters the ACC-posterior insula circuit and triggers changes in spinal networks that underlie nociceptive sensitization. Altogether, our results point to shared mechanisms underlying the comorbidity between ADHD and nociceptive sensitization. This interaction reinforces nociceptive sensitization and hyperactivity, suggesting that overlapping ACC circuits may be targeted to develop better treatments.
Topics: Animals; Attention Deficit Disorder with Hyperactivity; Disease Models, Animal; Gyrus Cinguli; Hyperalgesia; Impulsive Behavior; Mice; Optogenetics; Oxidopamine; Pain; Sympatholytics
PubMed: 35858441
DOI: 10.1073/pnas.2114094119 -
Cell Reports. Medicine Oct 2023Dyskinesia is involuntary movement caused by long-term medication with dopamine-related agents: the dopamine agonist 3,4-dihydroxy-L-phenylalanine (L-DOPA) to treat...
Dyskinesia is involuntary movement caused by long-term medication with dopamine-related agents: the dopamine agonist 3,4-dihydroxy-L-phenylalanine (L-DOPA) to treat Parkinson's disease (L-DOPA-induced dyskinesia [LID]) or dopamine antagonists to treat schizophrenia (tardive dyskinesia [TD]). However, it remains unknown why distinct types of medications for distinct neuropsychiatric disorders induce similar involuntary movements. Here, we search for a shared structural footprint using magnetic resonance imaging-based macroscopic screening and super-resolution microscopy-based microscopic identification. We identify the enlarged axon terminals of striatal medium spiny neurons in LID and TD model mice. Striatal overexpression of the vesicular gamma-aminobutyric acid transporter (VGAT) is necessary and sufficient for modeling these structural changes; VGAT levels gate the functional and behavioral alterations in dyskinesia models. Our findings indicate that lowered type 2 dopamine receptor signaling with repetitive dopamine fluctuations is a common cause of VGAT overexpression and late-onset dyskinesia formation and that reducing dopamine fluctuation rescues dyskinesia pathology via VGAT downregulation.
Topics: Mice; Animals; Dopamine Agonists; Levodopa; Dopamine; Antiparkinson Agents; Parkinsonian Disorders; Dyskinesia, Drug-Induced; Oxidopamine; gamma-Aminobutyric Acid
PubMed: 37774703
DOI: 10.1016/j.xcrm.2023.101208 -
Journal of Extracellular Vesicles Nov 2023Extracellular vesicles (EVs) play a crucial role in intercellular communication, participating in the paracrine trophic support or in the propagation of toxic molecules,...
Extracellular vesicles (EVs) play a crucial role in intercellular communication, participating in the paracrine trophic support or in the propagation of toxic molecules, including proteins. RTP801 is a stress-regulated protein, whose levels are elevated during neurodegeneration and induce neuron death. However, whether RTP801 toxicity is transferred trans-neuronally via EVs remains unknown. Hence, we overexpressed or silenced RTP801 protein in cultured cortical neurons, isolated their derived EVs (RTP801-EVs or shRTP801-EVs, respectively), and characterized EVs protein content by mass spectrometry (MS). RTP801-EVs toxicity was assessed by treating cultured neurons with these EVs and quantifying apoptotic neuron death and branching. We also tested shRTP801-EVs functionality in the pathologic in vitro model of 6-Hydroxydopamine (6-OHDA). Expression of RTP801 increased the number of EVs released by neurons. Moreover, RTP801 led to a distinct proteomic signature of neuron-derived EVs, containing more pro-apoptotic markers. Hence, we observed that RTP801-induced toxicity was transferred to neurons via EVs, activating apoptosis and impairing neuron morphology complexity. In contrast, shRTP801-EVs were able to increase the arborization in recipient neurons. The 6-OHDA neurotoxin elevated levels of RTP801 in EVs, and 6-OHDA-derived EVs lost the mTOR/Akt signalling activation via Akt and RPS6 downstream effectors. Interestingly, EVs derived from neurons where RTP801 was silenced prior to exposing them to 6-OHDA maintained Akt and RPS6 transactivation in recipient neurons. Taken together, these results suggest that RTP801-induced toxicity is transferred via EVs, and therefore, it could contribute to the progression of neurodegenerative diseases, in which RTP801 is involved.
Topics: Transcription Factors; Oxidopamine; Proteomics; Proto-Oncogene Proteins c-akt; Extracellular Vesicles
PubMed: 37932242
DOI: 10.1002/jev2.12378