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Neuronal impact of patient-specific aberrant NRXN1α splicing [targeted]

ABSTRACT: We performed targeted long-read and short-read RNA sequencing to identify and quantify NRXN1 isoforms in human post-mortem dlPFC and hiPSC-neurons derived from controls and NRXN1+/- individuals.

ORGANISM(S): Homo sapiens

PROVIDER: GSE137127 | GEO | 2019/09/10

REPOSITORIES: GEO

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Neuronal impact of patient-specific aberrant NRXN1α splicing [whole]

Project description:We performed targeted long-read and short-read RNA sequencing to identify and quantify NRXN1 isoforms in human post-mortem dlPFC and hiPSC-neurons derived from controls and NRXN1+/- individuals. We also performed whole transcriptome RNA seuqencing and 10x genomics single cell sequencing to determine transcriptional changes in NRXN1+/- hiPSC-neurons compared to controls.

2019-09-10 | GSE137101 | GEO

Schizophrenia: postmortem dorsal lateral prefrontal cortex (DLPFC)

Project description:RNA-Seq analysis of post-mortem tissue from DLPFC of 19 schizophrenia patients and 19 controls.

2016-12-30 | GSE87194 | GEO

Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models.

Project description: Not available

| S-EPMC6450673 | biostudies-literature

Targeted Degradation of Aberrant Tau in Frontotemporal Dementia Patient-Derived Neuronal Cell Models

Project description:Tauopathies are a family of neurodegenerative diseases characterized by a shared pathology of aberrant forms of tau protein accumulation leading to neuronal death in focal areas of the brain. Positron emission tomography (PET) tracers that bind to tau aggregates are used to aid diagnosis, but there are no current therapies to eliminate these tau species. We employed targeted protein degradation technology to convert a tau PET probe into a functional degrader of pathogenic tau. The hetero-bifunctional molecule QC-01- 175 was designed to engage both tau and Cereblon (CRBN), a substrate receptor for the Cullin-4 RING E3 ubiquitin ligase family member (CRL4CRBN), to trigger tau ubiquitination and proteasomal degradation. QC-01-175 effected clearance of tau in frontotemporal dementia (FTD) patient-derived neuronal cell models, which recapitulate disease phenotypes of tau accumulation, insolubility and toxicity. Furthermore, QC-01-175 had minimal effect on tau levels in neurons from healthy controls, indicating specificity for degradation of disease-relevant forms of tau. QC-01-175 also rescued vulnerability to stress in FTD neurons, phenocopying CRISPR-mediated MAPT-knockout. This work demonstrates that aberrant tau species formed in ex vivo FTD patient-derived neurons are amenable to targeted protein degradation, representing an important advance towards the development of a tau targeted therapeutic.

2019-03-26 | PXD012515 | Pride

Cross-Platform Validation of Neurotransmitter Release Impairments in Schizophrenia Patient-Derived NRXN1-Mutant Neurons

Project description:Heterozygous NRXN1 deletions constitute the most prevalent currently known single-gene mutation associated with schizophrenia, and predispose to multiple other neurodevelopmental disorders. Previous studies showed that engineered heterozygous NRXN1 deletions impaired neurotransmitter release in human neurons, suggesting a synaptic pathophysiological mechanism. Utilizing this observation for drug discovery, however, requires confidence in its robustness and validity. Here, we describe a multi-center effort to test the generality of this pivotal observation, using independent analyses at two laboratories of patient-derived and newly engineered human neurons with heterozygous NRXN1 deletions. We show that in neurons that were trans-differentiated from induced pluripotent stem cells derived from three NRXN1-deletion patients, the same impairment in neurotransmitter release was observed as in engineered NRXN1-deficient neurons. This impairment manifested as a decrease in spontaneous synaptic events and in evoked synaptic responses, and an alteration in synaptic paired-pulse depression. Nrxn1-deficient mouse neurons generated from embryonic stem cells by the same method as human neurons did not exhibit impaired neurotransmitter release, suggesting a human-specific phenotype. NRXN1 deletions produced a reproducible increase in the levels of CASK, an intracellular NRXN1-binding protein, and were associated with characteristic gene expression changes. Thus, heterozygous NRXN1 deletions robustly impair synaptic function in human neurons regardless of genetic background, enabling future drug discovery efforts.

2021-03-12 | GSE168762 | GEO

Neuronal impact of patient-specific aberrant NRXN1α splicing [targeted]

Project description:Neuronal impact of patient-specific aberrant NRXN1α splicing [targeted]

| PRJNA564596 | ENA

Neuronal impact of patient-specific aberrant NRXN1? splicing.

Project description: Not available

| S-EPMC7451045 | biostudies-literature

Gene expression in the human prefrontal cortex during postnatal development

Project description:Fresh frozen post mortem prefrontal cortex tissue (Brodman area 46) was obtained from 44 individuals varying in age from 0 to 49 years. RNA was extracted from these samples and hybridized to HG133plus2.0 GeneChips. The data was used to examine patterns of gene expression over the course of human postnatal developmental and ageing. PMI - postmortem interval, DLPFC - dorsolateral prefrontal cortex

2009-11-11 | GSE13564 | GEO

Transcription profiling of human prefrontal cortex during postnatal development

2009-12-02 | E-GEOD-13564 | biostudies-arrayexpress

Gene expression changes associated with Alexander disease (AxD)

Project description:We use human induced pluripotent stem cell (hiPSC)-derived astrocytes and post-mortem human brain tissues to study gene expression changes associated with AxD

2018-08-01 | GSE116327 | GEO

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