Zonisamide facilitates survival of human iPS cell-derived dopaminergic neurons in the rat striatum
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PROVIDER: PRJNA448563 | ENA |
REPOSITORIES: ENA
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Project description:It is reported that the transplantation of dopaminergic (DA) progenitors derived from pluripotent stem cells improves the behavior of Parkinson's disease (PD) model animals. However, the number of survived DA neurons was reported to be about 10% of the transplanted cells. This low survivability limits the clinical application of this stem cell-based therapy for PD. Recently, it was reported that zonisamide (ZNS) increased the number of survived DA neurons upon the transplantation of mouse induced pluripotent stem (iPS) cell-derived DA progenitors in the mouse striatum. It is not known, however, whether ZNS exerts the same effect on human DA neurons. We induced DA progenitors from human iPS cells and transplanted them into the rat striatum with daily administration of ZNS. The number of survived DA neurons was evaluated one and four months after transplantation by immunohistochemistry. To assess the mechanism of action of ZNS, we performed a microarray analysis to compare the gene expression profile in striatum treated with or without ZNS. The immunofluorescense study at one and four months revealed that the number of survived DA neurons was significantly increased with the administration of ZNS. The microarray analysis revealed that the expression of Slitrk6 was up-regulated in rat striatum treated with ZNS. SLIT and NTRK like protein 6 (SLITRK6) was expressed by cholinergic neurons in the striatum. In addition, survival and neurite extension were enhanced when human iPS cell-derived DA progenitors were cultured on SLITRK6-expressing HEK293T cells. ZNS promotes the survival of DA neurons after the transplantation of human iPS cell-derived DA progenitors in the rat striatum. SLITRK6 is suggested to be involved in this supportive effect of ZNS by modulating the environment of the host brain.
2019-04-26 | GSE112624 | GEO
Project description:Dopaminergic neurons located in the ventral Midbrain (vMid) innervate the striatum and cortex and are involved in movement control and reward-related cognition. Degeneration of dopaminergic neurons causes Parkinson’s disease (PD), while their over-activation is implicated in addiction. Thus, modeling the dopaminergic system is of broad relevance for disease research and drug discovery, although limited availability of patient material and inherent differences in animal model systems are restricting the study of distinctive human specific features such as development and neurodegeneration. Here, we show that spatially arranged assembloids can recapitulate dopaminergic innervation of striatum and cortex and offer methods for their use in cell replacement therapy and addiction research. We describe improved protocols for growing vMid, striatal and cortical organoids and use custom embedding molds to fuse them in a linear manner. Linear assembloids form functional long-range dopaminergic connections with striatal and cortical tissues that can release dopamine. We demonstrate that vMid grafts derived from hPSCs for cell replacement therapy of PD can integrate into the tissue and structurally mature. Additionally, we demonstrate that our model can be used to study dopaminergic circuit perturbations in the example of chronic cocaine treatment which causes morphological, functional and transcriptional changes that remained altered even after drug withdrawal. Our method opens new avenues for dopaminergic cell replacement therapy and the analysis of drugs affecting the dopaminergic system, directly in a human system.
2023-09-20 | GSE219246 | GEO
Project description:Dopaminergic neurons located in the ventral Midbrain (vMid) innervate the striatum and cortex and are involved in movement control and reward-related cognition. Degeneration of dopaminergic neurons causes Parkinson’s disease (PD), while their over-activation is implicated in addiction. Thus, modeling the dopaminergic system is of broad relevance for disease research and drug discovery, although limited availability of patient material and inherent differences in animal model systems are restricting the study of distinctive human specific features such as development and neurodegeneration. Here, we show that spatially arranged assembloids can recapitulate dopaminergic innervation of striatum and cortex and offer methods for their use in cell replacement therapy and addiction research. We describe improved protocols for growing vMid, striatal and cortical organoids and use custom embedding molds to fuse them in a linear manner. Linear assembloids form functional long-range dopaminergic connections with striatal and cortical tissues that can release dopamine. We demonstrate that vMid grafts derived from hPSCs for cell replacement therapy of PD can integrate into the tissue and structurally mature. Additionally, we demonstrate that our model can be used to study dopaminergic circuit perturbations in the example of chronic cocaine treatment which causes morphological, functional and transcriptional changes that remained altered even after drug withdrawal. Our method opens new avenues for dopaminergic cell replacement therapy and the analysis of drugs affecting the dopaminergic system, directly in a human system.
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2013-06-15 | E-GEOD-47215 | biostudies-arrayexpress
Project description:Here we use MeRIP-Seq to analyze global adenosine methylation (m6A) in mRNAs in the midbrain and striatum of Fto-deficient mice. We find that Fto deficiency leads to increased methylation within a subset of mRNAs important for neuronal signaling, including many within the dopaminergic signaling pathway. Collectively, our results show that Fto regulates demethylation of specific mRNAs in vivo, and this activity relates to control of dopaminergic transmission. Profiling of m6A in midbrain and striatum from FTO knockout mice
2013-06-15 | E-GEOD-47216 | biostudies-arrayexpress
Project description:We have generated isogenic induced pluripotent stem cell lines by reprogramming human fibroblasts from patients carrying the LRRK2 G2019S mutation with subsequent zinc finger nuclease - mediated targeted correction of the diseased allele. These iPS cell lines were differentiated for 30 days using a direct differentiation protocol towards midbrain dopaminergic neurons (mDANs). Isogenic human iPS cells carrying the LRRK2 WT and G2019S locus were differentiated to dopaminergic neurons to detect gene expression changes associated with mutated LRRK2.
2013-03-07 | E-GEOD-43364 | biostudies-arrayexpress
Project description:Disruption of local iron homeostasis is a common feature of neurodegenerative diseases. We focused on dopaminergic neurons, asking how iron transport proteins modulate iron homeostasis in vivo. Inactivation of the transmembrane iron exporter ferroportin had no apparent consequences. However, loss of the transferrin receptor 1, involved in iron uptake, caused profound, age-progressive neurodegeneration with features similar to Parkinson’s disease. There was gradual loss of dopaminergic projections in the striatum with subsequent death of dopaminergic neurons in the substantia nigra. After depletion of 30% of the neurons the mice developed neurobehavioral parkinsonism, with evidence of mitochondrial dysfunction and impaired mitochondrial autophagy. Molecular analysis revealed strong signatures indicative of attempted axonal regeneration, a metabolic switch to glycolysis and the unfolded protein response. We speculate that cellular iron deficiency may contribute to neurodegeneration in human patients Using Ribotag technology, from mouse ventral midbrain lysates, we isolated actively translated mRNA species from control and Transferrin receptor 1-null dopaminergic neurons. Two mouse ages were used 3 wks (early neurodegeration) 10 wks (late neurodegeneration)
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Project description:Dopaminergic projections to the ventral and dorsomedial striatum are important for reward, motivation, and goal-directed learning, whereas projections to the dorsolateral striatum are implicated in motor control, habitual enactment of motor skills, visuospatial learning, and memory. These conclusions are derived from studies of rodents with lesions or pharmacological blockade of dopamine signaling to specific brain regions. In contrast, we investigated the behavioral abilities of dopamine-deficient mice in which dopamine signaling was restored to only the medial striatum by viral rescue. These mice displayed intact spatial memory, visuospatial and discriminatory learning. However, acquisition of operant behavior was delayed, and their motivation to obtain food rewards was blunted. We compare these behavioral results with our published results obtained from mice with dopamine signaling restored only to the dorsolateral striatum. We observe that most behaviors are restored with dopamine signaling restored to either brain region and conclude that the action of dopamine in either one of these nonoverlapping striatal areas can support cognitive processes independently of dopamine signaling in the other area.
| S-EPMC3771669 | biostudies-literature
Project description:Here we use MeRIP-Seq to analyze global adenosine methylation (m6A) in mRNAs in the midbrain and striatum of Fto-deficient mice. We find that Fto deficiency leads to increased methylation within a subset of mRNAs important for neuronal signaling, including many within the dopaminergic signaling pathway. Collectively, our results show that Fto regulates demethylation of specific mRNAs in vivo, and this activity relates to control of dopaminergic transmission.
2013-06-15 | GSE47215 | GEO
Project description:To realize cell transplantation therapy for Parkinson's disease (PD), the grafted neurons should be integrated into the host neuronal circuit in order to restore the lost neuronal function. Here, using wheat germ agglutinin-based trans-synaptic tracing, we show that integrin α5 is selectively expressed in striatal neurons that are innervated by midbrain dopaminergic (DA) neurons from the mouse experiments. Additionally, we found that integrin α5β1 was activated by the administration of estradiol-2-benzoate (E2B) in striatal neurons of adult female rats. Importantly, we observed that the systemic administration of E2B into hemi-parkinsonian rat models facilitates the functional integration of grafted DA neurons derived from human induced pluripotent stem cells into the host striatal neuronal circuit via the activation of integrin α5β1. Finally, methamphetamine-induced abnormal rotation was recovered earlier in E2B-administrated rats than in rats that received other regimens. Our results suggest that the simultaneous administration of E2B with stem cell-derived DA progenitors can enhance the efficacy of cell transplantation therapy for PD. 0.5 µL of 1% WGA Alexa Fluor 488 solution was stereotactically injected into the bilateral SNpc (from the bregma: A -3.0, L ±1.2, V -4.2 and TB 0) of mouse. Two days after injection, a striatum sample was dissected from the mouse brain and dissociated into a single cell population by Accumax (Innovated Cell Technologies, Inc., CA, USA). To separate a two-cell population, Alexa Fluor 488+ cells and Alexa Fluor 488- cells were sorted using a FACSAria III cell sorter. Dead cells were identified and eliminated by 7-amino-actinomycin D (7-AAD) staining.
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