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PloS One 2014In patients with Parkinson's disease (PD), stem cells can serve as therapeutic agents to restore or regenerate injured nervous system. Here, we differentiated two types... (Comparative Study)
Comparative Study
In patients with Parkinson's disease (PD), stem cells can serve as therapeutic agents to restore or regenerate injured nervous system. Here, we differentiated two types of stem cells; mouse embryonic stem cells (mESCs) and protein-based iPS cells (P-iPSCs) generated by non-viral methods, into midbrain dopaminergic (mDA) neurons, and then compared the efficiency of DA neuron differentiation from these two cell types. In the undifferentiated stage, P-iPSCs expressed pluripotency markers as ES cells did, indicating that protein-based reprogramming was stable and authentic. While both stem cell types were differentiated to the terminally-matured mDA neurons, P-iPSCs showed higher DA neuron-specific markers' expression than ES cells. To investigate the mechanism of the superior induction capacity of DA neurons observed in P-iPSCs compared to ES cells, we analyzed histone modifications by genome-wide ChIP sequencing analysis and their corresponding microarray results between two cell types. We found that Wnt signaling was up-regulated, while SFRP1, a counter-acting molecule of Wnt, was more suppressed in P-iPSCs than in mESCs. In PD rat model, transplantation of neural precursor cells derived from both cell types showed improved function. The present study demonstrates that P-iPSCs could be a suitable cell source to provide patient-specific therapy for PD without ethical problems or rejection issues.
Topics: Animals; Cell Differentiation; Cell Movement; Cells, Cultured; Dopaminergic Neurons; Embryonic Stem Cells; Female; Gene Expression; Induced Pluripotent Stem Cells; Intercellular Signaling Peptides and Proteins; Membrane Proteins; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Microscopy, Confocal; Oxidopamine; Parkinson Disease, Secondary; Proteins; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Treatment Outcome; Wnt Proteins; Wnt Signaling Pathway; Wnt-5a Protein
PubMed: 24465672
DOI: 10.1371/journal.pone.0085736 -
Stem Cell Reports Nov 2018Neuronal subtype is largely fixed in the adult mammalian brain. Here, however, we unexpectedly reveal that adult mouse striatal neurons can be reprogrammed into...
Neuronal subtype is largely fixed in the adult mammalian brain. Here, however, we unexpectedly reveal that adult mouse striatal neurons can be reprogrammed into dopaminergic neuron-like cells (iDALs). This in vivo phenotypic reprogramming can be promoted by a stem cell factor (SOX2), three dopaminergic neuron-enriched transcription regulators (NURR1, LMX1A, and FOXA2), and a chemical compound (valproic acid). Although the site of action of the reprogramming factors remains to be determined, immunohistochemistry and genetic lineage mappings confirm striatal neurons as the cell origin for iDALs. iDALs exhibit electrophysiological properties stereotypical to endogenous dopaminergic rather than striatal neurons. Together, these results indicate that neuronal phenotype can be reengineered even in the adult brain, implicating a therapeutic strategy for neurological diseases.
Topics: Action Potentials; Aging; Animals; Biomarkers; Cell Proliferation; Cellular Reprogramming; Corpus Striatum; Dopaminergic Neurons; HEK293 Cells; Humans; Lateral Ventricles; Mice, Transgenic; Neuroglia; Phenotype
PubMed: 30318292
DOI: 10.1016/j.stemcr.2018.09.004 -
Neuroscience Feb 2018Serum response factor (SRF), a transcription factor highly expressed in neurons, is involved in neuronal survival and the pathogenesis of some neurodegenerative...
Serum response factor (SRF), a transcription factor highly expressed in neurons, is involved in neuronal survival and the pathogenesis of some neurodegenerative disorders. The ablation of SRF renders the midbrain dopaminergic (DA) neurons vulnerable to 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine-induced neurotoxicity, however, the underlying mechanisms remain poorly understood. Here, we report decreased SRF levels in the substantia nigra (SN) of rotenone-treated rats that was associated with the loss of tyrosine hydroxylase (TH)-positive neurons. SRF expression was also reduced in rotenone-treated PC12 cells in vitro. In addition, Srf knockdown augmented rotenone-induced toxicity in PC12 cells. In contrast, overexpression of Srf attenuated the cells' sensitivity to rotenone and alleviated rotenone-induced α-synuclein accumulation. The protective effect of SRF was abolished when the expression of autophagy-related proteins Beclin 1 and Atg5 was suppressed. These results suggested that SRF may promote DA neuron survival by regulating autophagy, and thus serves as a critical molecule in PD progression.
Topics: Animals; Autophagy; Autophagy-Related Protein 5; Beclin-1; Cell Survival; Dopaminergic Neurons; Male; PC12 Cells; Parkinsonian Disorders; Random Allocation; Rats; Rats, Inbred Lew; Rotenone; Substantia Nigra; Transcription Factors; Tyrosine 3-Monooxygenase; alpha-Synuclein
PubMed: 29196028
DOI: 10.1016/j.neuroscience.2017.11.040 -
Neurochemistry International Jan 2019Attention deficit hyperactivity disorder (ADHD) has a prevalence of 7.5% in school-age children in Taiwan. A number of ADHD patients start taking medications in...
Attention deficit hyperactivity disorder (ADHD) has a prevalence of 7.5% in school-age children in Taiwan. A number of ADHD patients start taking medications in elementary school and continue their treatment until they are in college or adulthood. Methylphenidate is the most frequently used medication prescribed for ADHD treatment. The influence of long-term treatment of methylphenidate on neuro-development, especially dopaminergic neurons, in rats would be explored. This study investigated the impact of long-term treatment of methylphenidate on different neurons. Rats aged 1 month were divided into three groups: Normal group receiving only sucrose solution, Low-dose group receiving 2 mg/kg methylphenidate, and High-dose group receiving 10 mg/kg methylphenidate; for each group, the drug was administrated twice per day. After 7 months of the treatment period, then the alterations in number of norepinephrine, serotonergic, cholinergic and dopaminergic neurons were quantified. The number of dopaminergic neurons in the substantia nigra (SN), the serotonergic neurons in the dorsal raphe nucleus, and the cholinergic neurons in the tegmental nucleus significantly decreased as compared with Normal group, whereas the noradrenergic neurons in the locus coeruleus substantially increased. The whole-cell recording was made from dopaminergic neurons residing in the SN for examination of their firing activity. The recorded dopaminergic neurons in SN were categorized into slow and fast firing using 10 Hz as a classified index. The results displayed that the ratio of dopaminergic neurons with fast firing in the High-dose group was less as compared with those in the Normal and the Low-dose group. Furthermore, the amplitude of action potential of the dopaminergic neurons with slow firing was higher in the High-dose group than those in the Normal and Low-dose groups. The firing behavior of dopaminergic neurons and dopamine concentration in the brain is affected by the long-term challenge of methylphenidate.
Topics: Action Potentials; Animals; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Dopamine; Dopaminergic Neurons; Male; Methylphenidate; Norepinephrine; Rats, Sprague-Dawley; Substantia Nigra; Time
PubMed: 30423424
DOI: 10.1016/j.neuint.2018.11.001 -
Neuropeptides Jun 2023Parkinson's disease is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta. The surviving nigral dopaminergic neurons... (Review)
Review
Parkinson's disease is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta. The surviving nigral dopaminergic neurons display altered spontaneous firing activity in Parkinson's disease. The firing rate of nigral dopaminergic neurons decreases long before complete neuronal death and the appearance of parkinsonian symptoms. A mild stimulation could rescue dopaminergic neurons from death and in turn play neuroprotective effects. Several neuropeptides, including cholecystokinin (CCK), ghrelin, neurotensin, orexin, tachykinins and apelin, within the substantia nigra pars compacta play important roles in the modulation of spontaneous firing activity of dopaminergic neurons and therefore involve motor control and motor disorders. Here, we review neuropeptide-induced modulation of the firing properties of nigral dopaminergic neurons. This review may provide a background to guide further investigations into the involvement of neuropeptides in movement control by modulating firing activity of nigral dopaminergic neurons in Parkinson's disease.
Topics: Humans; Dopaminergic Neurons; Parkinson Disease; Neuroprotection; Substantia Nigra; Neuropeptides
PubMed: 37087783
DOI: 10.1016/j.npep.2023.102337 -
Molecular Neurobiology Oct 2014The adult midbrain contains 75% of all dopaminergic neurons in the CNS. Within the midbrain, these neurons are divided into three anatomically and functionally distinct... (Review)
Review
The adult midbrain contains 75% of all dopaminergic neurons in the CNS. Within the midbrain, these neurons are divided into three anatomically and functionally distinct clusters termed A8, A9 and A10. The A9 group plays a functionally non-redundant role in the control of voluntary movement, which is highlighted by the motor syndrome that results from their progressive degeneration in the neurodegenerative disorder, Parkinson's disease. Despite 50 years of investigation, treatment for Parkinson's disease remains symptomatic, but an intensive research effort has proposed delivering neurotrophic factors to the brain to protect the remaining dopaminergic neurons, or using these neurotrophic factors to differentiate dopaminergic neurons from stem cell sources for cell transplantation. Most neurotrophic factors studied in this context have been members of the transforming growth factor β (TGFβ) superfamily. In recent years, an intensive research effort has focused on understanding the function of these proteins in midbrain dopaminergic neuron development and their role in the molecular architecture that regulates the development of this brain region, with the goal of applying this knowledge to develop novel therapies for Parkinson's disease. In this review, the current evidence showing that TGFβ superfamily members play critical roles in the regulation of midbrain dopaminergic neuron induction, differentiation, target innervation and survival during embryonic and postnatal development is analysed, and the implications of these findings are discussed.
Topics: Animals; Cell Differentiation; Dopaminergic Neurons; Humans; Mesencephalon; Nerve Growth Factors; Parkinson Disease; Transforming Growth Factor beta
PubMed: 24504901
DOI: 10.1007/s12035-014-8639-3 -
Journal of Pharmacological Sciences 2014The specific toxicity to dopaminergic neurons of psychostimulants and neurotoxins has been extensively studied in vivo and in vitro, and findings have been used to... (Review)
Review
The specific toxicity to dopaminergic neurons of psychostimulants and neurotoxins has been extensively studied in vivo and in vitro, and findings have been used to establish animal models of amphetamine psychosis or Parkinson's disease. The multiple mechanisms of neurotoxicity operating in these disorders are known to involve oxidative stress or neuroinflammation, producing the characteristic behavioral and neuropathlogical changes arising from injured dopaminergic neurons and glial cells. A number of studies have shown that glia-targeting antioxidants play important roles in protecting against the neurotoxicity caused by psychostimulants or neurotoxins. Phytochemicals, which are non-nutritive plant chemicals, protect dopaminergic neurons and glial cells from damage caused by psychostimulants or neurotoxins. The objective of this review was to evaluate the involvement of glial cells in dopaminergic neuron-specific toxicity and to explore the neuroprotective activity of phytochemicals in terms of anti-inflammatory and antioxidant action.
Topics: Animals; Antioxidants; Catechin; Cyclooxygenase 2; Dopamine; Dopaminergic Neurons; Flavonoids; Humans; Methamphetamine; Microglia; Nerve Degeneration; Neuroprotective Agents; Neurotoxins; Phytochemicals; Polyphenols; Reactive Oxygen Species
PubMed: 24599140
DOI: 10.1254/jphs.13r19cp -
Cell Reports Jun 2014To determine the long-term health and function of transplanted dopamine neurons in Parkinson's disease (PD) patients, the expression of dopamine transporters (DATs) and...
To determine the long-term health and function of transplanted dopamine neurons in Parkinson's disease (PD) patients, the expression of dopamine transporters (DATs) and mitochondrial morphology were examined in human fetal midbrain cellular transplants. DAT was robustly expressed in transplanted dopamine neuron terminals in the reinnervated host putamen and caudate for at least 14 years after transplantation. The transplanted dopamine neurons showed a healthy and nonatrophied morphology at all time points. Labeling of the mitochondrial outer membrane protein Tom20 and α-synuclein showed a typical cellular pathology in the patients' own substantia nigra, which was not observed in transplanted dopamine neurons. These results show that the vast majority of transplanted neurons remain healthy for the long term in PD patients, consistent with clinical findings that fetal dopamine neuron transplants maintain function for up to 15-18 years in patients. These findings are critically important for the rational development of stem-cell-based dopamine neuronal replacement therapies for PD.
Topics: Dopamine Plasma Membrane Transport Proteins; Dopaminergic Neurons; Humans; Parkinson Disease
PubMed: 24910427
DOI: 10.1016/j.celrep.2014.05.027 -
Cellular Reprogramming Oct 2020Mesenchymal stem cells (MSCs) have the potential to differentiate into neuron-like cells, which may provide a new strategy for the clinical treatment of...
Mesenchymal stem cells (MSCs) have the potential to differentiate into neuron-like cells, which may provide a new strategy for the clinical treatment of neurodegenerative diseases such as Parkinson's disease (PD). However, the application of MSCs in the patients is still limited as the reason of efficiency and safety of transplantation. The aim of this study is to develop a new method and induce human umbilical cord MSCs (hUCMSCs) into neuron-like cells. Results from flow cytometry indicate that the isolated MSCs from hUCMSCs exhibited a typical phenotype of adult stem cells and express CD44, CD54, CD73, CD90, CD105, CD166, and HLA-ABC. Furthermore, the induced cells from hUCMSCs could spontaneously express different neural cell markers [neuron-specific enolase (NSE) and glial fibrillary acidic protein (GFAP)], even transcription factors related to dopaminergic neuron's development (Nurr1, Wnt-1, and En-1). Moreover, after treatment of EHFBT (extracts of human fetal brain tissue), hUCMSCs can express neuronal markers such as Nestin, LIM homeobox transcription factor 1 beta (LMX1B), dopamine beta hydroxylase (DBH), and dopamine transporter (DAT). In summary, a method that can induce hUCMSCs into dopaminergic neuron containing cells is established by the treatment of EHFBT. This would provide us a new cell source for PD in clinical treatment in the future.
Topics: Biomarkers; Brain; Brain Chemistry; Cell Differentiation; Cells, Cultured; Cellular Reprogramming Techniques; Dopaminergic Neurons; Fetus; Humans; Mesenchymal Stem Cells; Tissue Extracts; Umbilical Cord
PubMed: 32833524
DOI: 10.1089/cell.2020.0029 -
FEBS Letters Dec 2015The homeoprotein Engrailed (Engrailed-1/Engrailed-2, collectively En1/2) is not only a survival factor for mesencephalic dopaminergic (mDA) neurons during development,... (Review)
Review
The homeoprotein Engrailed (Engrailed-1/Engrailed-2, collectively En1/2) is not only a survival factor for mesencephalic dopaminergic (mDA) neurons during development, but continues to exert neuroprotective and physiological functions in adult mDA neurons. Loss of one En1 allele in the mouse leads to progressive demise of mDA neurons in the ventral midbrain starting from 6 weeks of age. These mice also develop Parkinson disease-like motor and non-motor symptoms. The characterization of En1 heterozygous mice have revealed striking parallels to central mechanisms of Parkinson disease pathogenesis, mainly related to mitochondrial dysfunction and retrograde degeneration. Thanks to the ability of homeoproteins to transduce cells, En1/2 proteins have also been used to protect mDA neurons in various experimental models of Parkinson disease. This neuroprotection is partly linked to the ability of En1/2 to regulate the translation of certain nuclear-encoded mitochondrial mRNAs for complex I subunits. Other transcription factors that govern mDA neuron development (e.g. Foxa1/2, Lmx1a/b, Nurr1, Otx2, Pitx3) also continue to function for the survival and maintenance of mDA neurons in the adult and act through partially overlapping but also diverse mechanisms.
Topics: Animals; Dopaminergic Neurons; Homeodomain Proteins; Humans; Mice, Transgenic; Mitochondria; Nerve Tissue Proteins; Parkinson Disease
PubMed: 26459030
DOI: 10.1016/j.febslet.2015.10.002