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Physiological Research Mar 2019Parkinson's disease (PD), which is the second most common neurodegenerative disorder after Alzheimer's disease, is firstly defined after James Parkinson's report. It... (Review)
Review
Parkinson's disease (PD), which is the second most common neurodegenerative disorder after Alzheimer's disease, is firstly defined after James Parkinson's report. It carries motor symptoms such as resting tremor, bradykinesia and rigidity of skeletal muscle and freezing of gait. Furthermore, non-motor symptoms such as cognitive and behavioral problems, besides sensory impairments are seen in the patients. However, they may also suffer from sleep disorders or autonomic dysfunction. Although there are some medications in order to symptomatic management, but unfortunately, scientist could not have found exact approaches to cure this disease. Hence, producing a model which can express the most pathophysiologic and behavioral aspects of the disease is a desire. In this paper, we aimed to describe the different models of Parkinson's disease in brief.
Topics: Animals; Disease Models, Animal; Humans; MPTP Poisoning; Oxidopamine; Parkinson Disease
PubMed: 30433804
DOI: 10.33549/physiolres.933895 -
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 -
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 -
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 -
International Journal of Molecular... Nov 2013Since their discovery, Parkinsonian toxins (6-hydroxydopamine, MPP+, paraquat, and rotenone) have been widely employed as in vivo and in vitro chemical models of... (Review)
Review
Since their discovery, Parkinsonian toxins (6-hydroxydopamine, MPP+, paraquat, and rotenone) have been widely employed as in vivo and in vitro chemical models of Parkinson's disease (PD). Alterations in mitochondrial homeostasis, protein quality control pathways, and more recently, autophagy/mitophagy have been implicated in neurotoxin models of PD. Here, we highlight the molecular mechanisms by which different PD toxins dysregulate autophagy/mitophagy and how alterations of these pathways play beneficial or detrimental roles in dopamine neurons. The convergent and divergent effects of PD toxins on mitochondrial function and autophagy/mitophagy are also discussed in this review. Furthermore, we propose new diagnostic tools and discuss how pharmacological modulators of autophagy/mitophagy can be developed as disease-modifying treatments for PD. Finally, we discuss the critical need to identify endogenous and synthetic forms of PD toxins and develop efficient health preventive programs to mitigate the risk of developing PD.
Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Autophagy; Humans; MPTP Poisoning; Methamphetamine; Mitophagy; Neurotoxins; Oxidopamine; Paraquat; Parkinsonian Disorders; Rotenone
PubMed: 24217228
DOI: 10.3390/ijms141122163 -
The FEBS Journal Apr 2012Animal models of Parkinson's disease (PD) have been widely used in the past four decades to investigate the pathogenesis and pathophysiology of this neurodegenerative... (Review)
Review
Animal models of Parkinson's disease (PD) have been widely used in the past four decades to investigate the pathogenesis and pathophysiology of this neurodegenerative disorder. These models have been classically based on the systemic or local (intracerebral) administration of neutoxins that are able to replicate most of the pathological and phenotypic features of PD in mammals (i.e. rodents or primates). In the last decade, the advent of the 'genetic era' of PD has provided a phenomenal enrichment of the research possibilities in this field, with the development of various mammalian (mice and, more recently, rats) and non-mammalian transgenic models that replicate most of the disease-causing mutations identified for monogenic forms of familial PD. Both toxic and transgenic classes of animal PD models have their own specificities and limitations, which must be carefully taken into consideration when choosing the model to be used. If a substantial and reproducible nigrostriatal lesion is required (e.g. for testing therapeutic interventions aimed at counteracting PD-related cell death), a classic toxic model such as one based on the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or 6-hydroxydopamine will adequately serve the purpose. On the other hand, if selected molecular mechanisms of PD pathogenesis must be investigated, transgenic models will offer invaluable insights. Therefore, until the 'perfect' model is developed, indications to use one model or another will depend on the specific objectives that are being pursued.
Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Animals, Genetically Modified; Disease Models, Animal; Dopamine Agents; Herbicides; Humans; Neurotoxins; Oxidopamine; Paraquat; Parkinson Disease; Parkinson Disease, Secondary; Sympatholytics; alpha-Synuclein
PubMed: 22251459
DOI: 10.1111/j.1742-4658.2012.08491.x -
International Journal of Molecular... Jul 2023Parkinson's Disease (PD), treated with the dopamine precursor l-3,4-dihydroxyphenylalanine (L-DOPA), displays motor and non-motor orofacial manifestations. We...
Parkinson's Disease (PD), treated with the dopamine precursor l-3,4-dihydroxyphenylalanine (L-DOPA), displays motor and non-motor orofacial manifestations. We investigated the pathophysiologic mechanisms of the lateral pterygoid muscles (LPMs) and the trigeminal system related to PD-induced orofacial manifestations. A PD rat model was produced by unilateral injection of 6-hydroxydopamine into the medial forebrain bundle. Abnormal involuntary movements (dyskinesia) and nociceptive responses were determined. We analyzed the immunodetection of Fos-B and microglia/astrocytes in trigeminal and facial nuclei and morphological markers in the LPMs. Hyperalgesia response was increased in hemiparkinsonian and dyskinetic rats. Hemiparkinsonism increased slow skeletal myosin fibers in the LPMs, while in the dyskinetic ones, these fibers decreased in the contralateral side of the lesion. Bilateral increased glycolytic metabolism and an inflammatory muscle profile were detected in dyskinetic rats. There was increased Fos-B expression in the spinal nucleus of lesioned rats and in the motor and facial nucleus in L-DOPA-induced dyskinetic rats in the contralateral side of the lesion. Glial cells were increased in the facial nucleus on the contralateral side of the lesion. Overall, spinal trigeminal nucleus activation may be associated with orofacial sensorial impairment in Parkinsonian rats, while a fatigue profile on LPMs is suggested in L-DOPA-induced dyskinesia when the motor and facial nucleus are activated.
Topics: Rats; Animals; Levodopa; Dyskinesia, Drug-Induced; Corpus Striatum; Parkinsonian Disorders; Parkinson Disease; Oxidopamine; Brain Stem; Disease Models, Animal; Antiparkinson Agents
PubMed: 37569642
DOI: 10.3390/ijms241512270