Human iPSC-derived neurons reveal NMDAR-independent dysfunction following HIV-associated insults
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ABSTRACT:
PROVIDER: PRJNA1054618 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27292349_1.fastq.gz | Fastqsanger.gz | |||
| SRR27292349_2.fastq.gz | Fastqsanger.gz | |||
| SRR27292350_1.fastq.gz | Fastqsanger.gz | |||
| SRR27292350_2.fastq.gz | Fastqsanger.gz | |||
| SRR27292351_1.fastq.gz | Fastqsanger.gz |
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Project description:The central nervous system encounters a number of challenges following HIV infection, leading to increased risk for a collection of neurocognitive symptoms clinically classified as HIV-associated neurocognitive disorders (HAND). Studies attempting to identify causal mechanisms and potential therapeutic interventions have historically relied on primary rodent neurons, but a number of recent reports take advantage of iPSC-derived neurons in order to study these mechanisms in a readily-reproducible, human model. We found that iPSC-derived neurons differentiated via an inducible neurogenin-2 transcription factor were resistant to gross toxicity from a number of HIV-associated insults previously reported to be toxic in rodent models, including HIV-infected myeloid cell supernatants and the integrase inhibitor antiretroviral drug, elvitegravir. Further examination of these cultures revealed robust resistance to NMDA receptor-mediated toxicity. We then performed a comparative analysis of iPSC neurons exposed to integrase inhibitors and activated microglial supernatants to study sub-cytotoxic alterations in micro electrode array (MEA)-measured neuronal activity and gene expression, identifying extracellular matrix interaction/morphogenesis as the most consistently altered pathways across HIV-associated insults. These findings illustrate that HIV-associated insults dysregulate human neuronal activity and organization even in the absence of gross NMDA-mediated neurotoxicity, which has important implications on the effects of these insults in neurodevelopment and on the interpretation of primary vs. iPSC in vitro neuronal studies.
2024-01-20 | GSE250609 | GEO
Project description:The central nervous system encounters a number of challenges following HIV infection, leading to increased risk for a collection of neurocognitive symptoms clinically classified as HIV-associated neurocognitive disorders (HAND). Studies attempting to identify causal mechanisms and potential therapeutic interventions have historically relied on primary rodent neurons, but a number of recent reports take advantage of iPSC-derived neurons in order to study these mechanisms in a readily reproducible, human model. We found that iPSC-derived neurons differentiated via an inducible neurogenin-2 transcription factor were resistant to gross toxicity from a number of HIV-associated insults previously reported to be toxic in rodent models, including HIV-infected myeloid cell supernatants and the integrase inhibitor antiretroviral drug, elvitegravir. Further examination of these cultures revealed robust resistance to NMDA receptor-mediated toxicity. We then performed a comparative analysis of iPSC neurons exposed to integrase inhibitors and activated microglial supernatants to study sub-cytotoxic alterations in micro electrode array (MEA)-measured neuronal activity and gene expression, identifying extracellular matrix interaction/morphogenesis as the most consistently altered pathways across HIV-associated insults. These findings illustrate that HIV-associated insults dysregulate human neuronal activity and organization even in the absence of gross NMDA-mediated neurotoxicity, which has important implications on the effects of these insults in neurodevelopment and on the interpretation of primary vs. iPSC in vitro neuronal studies.
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Project description:Specific autoantibodies against the NMDA-receptor (NMDAR) GluN1 subunit cause severe and debilitating NMDAR-encephalitis. Autoantibodies induce prototypic disease symptoms resembling schizophrenia, including psychosis and cognitive dysfunction. Using a mouse passive transfer model applying human monoclonal anti-GluN1-autoantibodies, we observed CA1 pyramidal neuron hypoexcitability, reduced AMPA-receptor (AMPAR) signaling, and faster synaptic inhibition resulting in disrupted excitatory-inhibitory balance. Functional alterations were supported by widespread remodeling of the hippocampal proteome, including changes in glutamatergic and GABAergic neurotransmission. At the network level, anti-GluN1-autoantibodies amplified gamma oscillations and disrupted theta-gamma coupling. A data-informed network model revealed that lower AMPAR strength and faster GABAA-receptor current kinetics chiefly account for these abnormal oscillations. As predicted by our model and evidenced experimentally, positive allosteric modulation of AMPARs alleviated aberrant gamma activity and thus reinforced the causative effects of the excitatory-inhibitory imbalance. Collectively, NMDAR-hypofunction-induced aberrant synaptic, cellular, and network dynamics provide new mechanistic insights into disease symptoms in NMDAR-encephalitis and schizophrenia.
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Project description:Tau protein has critical roles in Alzheimer’s disease (AD) pathogenesis and neuronal excitation. Among tau gene mutations, A152T is reported to increase the risk of AD and neuronal excitability in mouse models. To examine the effects of tau gene mutations on neuronal excitability in human neurons, we introduced A152T or P301S mutation to induced pluripotent stem cells (iPSCs) using genome editing technology. To examine the effects of tau expression itself, we generated tau knockout or tau conjugate with a fluorescent protein. In excitatory neuronal culture, we found that the A152T mutation increases spontaneous neuronal excitation and the association of tau and Fyn. NMDAR antagonist blocked neuronal excitation in both the control and A152T neurons, indicating that the A152T mutation enhanced the intrinsic function of tau. Transcriptome analysis revealed structural changes by the A152T mutation. These data showed that the A152T tau gene mutation increases neuronal excitability through the tau-FYN-NMDAR pathway in excitatory neurons.
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Project description:Tau-A152T linked to AD induces neuronal hyperexcitation through FYN-NMDAR in human iPSC-neurons
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Project description:Genetic linkage analysis suggested that GKAP, a scaffold protein of the NMDA receptor (NMDAR), was a potential modifier of invasion in a mouse model of pancreatic neuroendocrine cancer (PanNET). Here we establish that GKAP governs invasive growth and treatment response of PanNET via its pivotal role in regulating the NMDAR pathway activity. Combining genetic knockdown of GKAP and pharmacological inhibition of NMDAR, we distilled gene expression signatures orchestrated by the NMDAR-GKAP axis, in addition to identifying two downstream effectors FMRP and HSF-1. Additionally, GKAP, FMRP, and HSF1 are functionally implicated in invasiveness of pancreatic ductal adenocarcinoma. Finally, gene expression signatures in tumors with low NMDAR activity are significantly associated with favorable patient prognosis in several cancer types.
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Project description:The study revealed differentially expressed lncRNAs in synaptic and extrasynaptic NMDAR activation and suggested that lncRNAs might be responsible for extrasynaptic NMDAR-induced neurodegeneration
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Project description:Purpose: To identify significantly differentially expressed genes and to investigate the intricate molecular regulatory network underlying anti-NMDA receptor encephalitis associated with ovarian teratoma. Methods: This retrospective study analyzed ovarian teratoma samples from patients with and without NMDAR-E. We employed RNA sequencing for gene expression profiling. qPCR and Western blotting were used for gene and protein expression validation. Results: We identified 2524 significantly differentially expressed genes. The changes were notable in mRNA levels in ovarian teratomas associated with NMDAR-E. Functional enrichment analysis highlighted extracellular matrix and immune activation pathways. Key genes and proteins involved in ferroptosis and immune activation, including SLC40A1, GGH, FKBP11, CCDC80, and ANK3, showed significant expression differences.Conclusions: Our findings offer deeper insights into the pathophysiology of NMDAR-encephalitis associated with ovarian teratomas. The identified biomarkers, particularly in ferroptosis and immune activation pathways, provide potential targets for diagnosis and treatment.
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Project description:To investigate the changes of the transcriptome in neuronal cells under the condition of NMDAR hypofunction and H/R injury, we compared the changes of mRNA and lncRNA expression levels in mouse hippocampal neuron HT22 cell with or without NMDAR knockdown and H/R stimulation by RNA sequencing.
2022-10-10 | GSE214716 | GEO
Project description:Elevated c-Jun levels result in apoptosis and are evident in neurodegenerative disorders such as Alzheimer's disease and dementia and after global cerebral insults such as stroke and epilepsy. NMDA receptor (NMDAR) antagonists block c-Jun upregulation and prevent neuronal cell death following excitotoxic insults. However, little is known about the molecular mechanisms that regulate c-Jun abundance in neurons. Here we show that PRR7, a component of synaptic junctions, can upregulate c-Jun levels by inhibiting its ubiquitination in neurons. PRR7 interacts with the GLUN1 subunit of NMDARs and is upregulated in the nucleus following NMDAR activation. We show that PRR7 interacts with the E3 ligase SCFFBW7 (FBW7) and blocks the FBW7-mediated ubiquitination of c-Jun. PRR7 overexpression increases c-Jun-dependent transcriptional activity and promotes neuronal death. Microarray assays indicate that both Prr7 knockdown or overexpression alter the abundance of c-Jun-regulated transcripts associated with cellular viability as well as synaptic function. Moreover, Prr7 knockdown attenuates NMDA-mediated excitotoxicity in primary neuronal cultures. Our results show that PRR7 links NMDAR activity to c-Jun function and provide insight into the processes that underlie NMDA-dependent excitotoxicity. Four biological replicas of each of the four conditions: NO = not transduced with virus; NT = transduced with control lentiviruses containing a non-targeting shRNA sequence; KD = transduced with lentiviruses expressing PRR7-specific shRNAs; OE= transduced with lentiviruses to overexpress PRR7.
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