Autism patient derived SHANK2BY29X mutation affects ALDH1A1 negative dopamine neuron development
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ABSTRACT:
PROVIDER: PRJNA1078417 | ENA |
REPOSITORIES: ENA
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Project description:Autism spectrum disorder (ASD) includes a series of neurodevelopmental conditions. Different mutations on a single ASD gene contribute to heterogeneous disease phenotypes, possibly due to functional diversity of generated isoforms. Increasing evidence indicates such phenomenon in SHANK2, a causative gene in ASD; however, there is a scarcity of tools for studying endogenous SHANK2 proteins in an isoform-specific manner. Here we reported a patient-derived mutation on SHANK2, hitting only the SHANK2B transcript variant (NM_133266.5), hereby SHANK2BY29X.
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Project description:Cas9 screen to enhance survival of postmitotic dopamine neurons in vivo. We identified TP53-mediated apoptotic cell death as major contributor to dopamine neuron loss and uncovered a causal link of TNFa-NFκB signaling in limiting cell survival. A surface marker screen enabled the purification of midbrain dopamine neurons obviating the need for genetic reporters. Combining cell sorting with adalimumab pretreatment, a clinically approved TNFa inhibitor, enabled efficient engraftment of postmitotic dopamine neurons leading to extensive re-innervation and functional recovery in a preclinical PD mouse model. Thus, transient TNFa inhibition may present a clinically relevant strategy to enhance survival of human PSC-derived lineages in PD and beyond.
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Project description:Midbrain dopamine (mDA) neurons play an essential role in cognitive and motor behaviours and are linked to different brain disorders. However, the molecular mechanisms underlying their development, and in particular the role of long non-coding RNAs (lncRNAs), remain incompletely understood. Here, we establish the transcriptomic landscape and alternative splicing patterns of linear and circular ncRNAs (lncRNAs and circRNAs) at key developmental timepoints in mouse mDA neurons using short and long-read RNAseq. Spatial analysis shows strong and subregion-specific expression of circRmst in mDA neurons and its post-transcriptional silencing affects soma size, TH+ neuron number, and mDA neuron positioning. Time-laps imaging indeed reveals that circRmst inhibits migration speed in developing mDA neurons. Together, these data for the first time establish a functional role for circRNAs in mDA neurons, further characterize poorly defined aspects of mDA neuron development, and provide a unique framework for future interrogation of lncRNAs in developing mDA neurons.
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Project description:Background: Methylphenidate (MPH) a psychostimulant prescribed to manage ADHD symptoms, has been increasingly prescribed to children not meeting the strict criteria for ADHD. It has also been misused as a “cognitive enhancer” and as an alternative to other psychostimulants. Here, we investigate whether chronic or acute administration of methylphenidate in mice at either 1mg/kg or 10mg/kg dosing, affects cell number and gene expression in the basal ganglion. Methodology/Principal findings: Through the use of stereological counting methods, we observed a significant reduction (~20%) in dopamine neuron numbers in the substantia nigra pars compacta (SNpc) following chronic administration of 10mg/kg MPH. This dosage of MPH also induced a significant increase in the number of morphologically-activated SNpc microglia. Additionally, exposure to either 1mg/kg or 10 mg/kg MPH increased the sensitivity of SNpc dopamine neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced oxidative stress. Unbiased gene screening employing Affymetrix GeneChip® HT MG-430 PM revealed changes in 115 and 54 genes in the substantia nigra (SN) of mice exposed to 1mg/kg and 10mg/kg MPH doses, respectively. Decreases in the mRNA levels of gdnf, dat1, vmat2 and th in the substantia nigra (SN) was observed with both acute and chronic dosing of 10mg/kg MPH. We also found an increase in mRNA levels of the pro-inflammatory genes il-6 and tnf-α in the striatum; although these were seen only at an acute dose of 10mg/kg and not following chronic dosing. Conclusion: Collectively our results suggest that chronic MPH usage in mice, especially at prolonged higher doses, has long-term neurodegenerative consequences. drug treatment: 3 control, 3 low dose treatment, 3 high dose treatment
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Project description:First-in-human clinical trials illustrate the feasibility and translational potential of human pluripotent stem cell (hPSC)-based cell therapy in Parkinson’s disease (PD). However, a major unresolved challenge is the extensive cell death following transplantation with <10% of grafted dopamine neurons surviving. Here, we performed a pooled CRISPR/Cas9 screen to enhance survival of postmitotic dopamine neurons in vivo. We identified TP53-mediated apoptotic cell death as major contributor to dopamine neuron loss and uncovered a causal link of TNFa-NFκB signaling in limiting cell survival. A surface marker screen enabled the purification of midbrain dopamine neurons obviating the need for genetic reporters. Combining cell sorting with adalimumab pretreatment, a clinically approved TNFa inhibitor, enabled efficient engraftment of postmitotic dopamine neurons leading to extensive re-innervation and functional recovery in a preclinical PD mouse model. Thus, transient TNFa inhibition may present a clinically relevant strategy to enhance survival of human PSC-derived lineages in PD and beyond.
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Project description:First-in-human clinical trials illustrate the feasibility and translational potential of human pluripotent stem cell (hPSC)-based cell therapy in Parkinson’s disease (PD). However, a major unresolved challenge is the extensive cell death following transplantation with <10% of grafted dopamine neurons surviving. Here, we performed a pooled CRISPR/Cas9 screen to enhance survival of postmitotic dopamine neurons in vivo. We identified TP53-mediated apoptotic cell death as major contributor to dopamine neuron loss and uncovered a causal link of TNFa-NFκB signaling in limiting cell survival. A surface marker screen enabled the purification of midbrain dopamine neurons obviating the need for genetic reporters. Combining cell sorting with adalimumab pretreatment, a clinically approved TNFa inhibitor, enabled efficient engraftment of postmitotic dopamine neurons leading to extensive re-innervation and functional recovery in a preclinical PD mouse model. Thus, transient TNFa inhibition may present a clinically relevant strategy to enhance survival of human PSC-derived lineages in PD and beyond.
2024-04-26 | GSE216364 | GEO
Project description:Midbrain dopamine (mDA) neurons play an essential role in cognitive and motor behaviours and are linked to different brain disorders. However, the molecular mechanisms underlying their development, and in particular the role of long non-coding RNAs (lncRNAs), remain incompletely understood. Here, we establish the transcriptomic landscape and alternative splicing patterns of linear and circular ncRNAs (lncRNAs and circRNAs) at key developmental timepoints in mouse mDA neurons using RNAseq at different time points during early development. Spatial analysis shows strong and subregion-specific expression of circRmst in mDA neurons and its post-transcriptional silencing affects soma size, TH+ neuron number, and mDA neuron positioning. Time-laps imaging indeed reveals that circRmst inhibits migration speed in developing mDA neurons. Together, these data for the first time establish a functional role for circRNAs in mDA neurons, further characterize poorly defined aspects of mDA neuron development, and provide a unique framework for future interrogation of lncRNAs in developing mDA neurons.
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Project description:Autism spectrum disorder (ASD) affects gene expression in adult ages. We used valproic acid (VPA)-induced ASD model marmosets. Gene expression modulations in VPA-exposed and unexposed (UE) marmosets were analyzed at adult ages. We revealed modulations in neuron- and glia-related genes.
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Project description:The metronome-like circadian regulation of sleep timing must still adapt to an uncertain environment. Recent studies in Drosophila indicate that neuromodulation not only plays a key role in clock neuron synchronization but also affects interactions between the clock network and brain sleep centers. We show here that the targets of neuromodulators, G-Protein Coupled Receptors (GPCRs), are highly enriched in the fly brain circadian clock network. Single cell sequencing indicates that they are not only enriched, but they are also differentially expressed and contribute to clock neuron identity. We generated a comprehensive guide library to mutagenize individual GPCRs in specific neurons and verified the strategy by introducing a targeted sequencing approach. Combined with a behavioral screen, the mutagenesis strategy revealed a novel role of dopamine in sleep regulation by identifying two dopamine receptors and a clock neuron subpopulation that gate the timing of sleep.
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Project description:G2019S mutaion of LRRK2 is known to increase mRNA translation. We perform ribosome profiling to study defective translation using human dopamine neuron models. Patient-derived human dopamine neurons with G2019S LRRK2 mutation were generated and used. Also a mutation-corrected isogenic pair line was used.
2018-07-01 | GSE90469 | GEO