A deep phenotyping study in mouse and iPSC models to understand the role of oligodendroglia in optic neuropathy in Wolfram syndrome(WS)
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1101498 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28723102.fastq.gz | Fastqsanger.gz | |||
| SRR28723103.fastq.gz | Fastqsanger.gz | |||
| SRR28723104.fastq.gz | Fastqsanger.gz | |||
| SRR28723105.fastq.gz | Fastqsanger.gz | |||
| SRR28723106.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 24 |
Similar Datasets
Project description:Oligodendrocyte progenitor cells (OPCs) derived from two WS patient lines (c2002_mutant and 2010_Mutant) and their respective isogenic line (Cl7_Ctrl and 2g6_Ctrl) were sequenced to determine transcriptomic differences
2024-09-30 | GSE264222 | GEO
Project description:Wolfram syndrome (WS) is a rare childhood disease characterized by diabetes mellitus, diabetes insipidus, blindness, deafness, neurodegeneration and eventually early death, due to autosomal recessive mutations in the WFS1 (and WFS2) gene. While it is categorized as a neurodegenerative disease, it is increasingly becoming clear that other cell types besides neurons may be affected and contribute to the pathogenesis. MRI studies in patients and phenotyping studies in WS rodent models indicate white matter/myelin loss, implicating a role for oligodendroglia in WS-associated neurodegeneration. In this study, we sought to determine if oligodendroglia are affected in WS and whether their dysfunction may be the primary cause of the observed optic neuropathy and brain neurodegeneration. We demonstrate that 7.5-month-old Wfs1∆exon8 mice display signs of abnormal myelination and a reduced number of oligodendrocyte precursor cells (OPCs) as well as abnormal axonal conduction in the optic nerve. An MRI study of the brain furthermore revealed grey and white matter loss in the cerebellum, brainstem, and superior colliculus, as is seen in WS patients. To further dissect the role of oligodendroglia in WS, we performed a transcriptomics study of WS patient iPSC-derived OPCs and pre-myelinating oligodendrocytes. Transcriptional changes compared to isogenic control cells were found for genes with a role in ER function. However, a deep phenotyping study of these WS patient iPSC-derived oligodendroglia unveiled normal differentiation, mitochondria-associated endoplasmic reticulum (ER) membrane interactions and mitochondrial function, and no overt signs of ER stress. Overall, the current study indicates that oligodendroglia functions are largely preserved in the WS mouse and patient iPSC-derived models used in this study. These findings do not support a major defect in oligodendroglia function as the primary cause of WS, and warrant further investigation of neurons and neuron-oligodendroglia interactions as a target for future neuroprotective or -restorative treatments for WS.
| S-EPMC11351506 | biostudies-literature
Project description:Pancreatic β-cell failure induced by WFS1 deficiency is manifested in wolfram syndrome (WS). The lack of a suitable human model in WS has hampered the progress in developing new treatments. Here, human pluripotent stem cell derived pancreatic β cells (SC-β cells) harboring WFS1-deficiency and mouse model of β cell-specific Wfs1 knockout were applied to model β-cell failure in WS. Single-cell RNA sequencing of WFS1-deficient SC-β cells revealed two cell fates along pseudotime trajectory including maturation and stress branch. WFS1 deficiency blocked β-cell fate trajectory to maturation but pushed it towards stress trajectory leading to β-cell failure.
2024-01-30 | GSE235331 | GEO
Project description:Aeromonas media WS strain:WS Genome sequencing
| PRJNA170164 | ENA
Project description:Cupriavidus sp. WS strain:WS Genome sequencing and assembly
| PRJNA195550 | ENA
Project description:Wolfram syndrome is a rare genetic disorder largely caused by pathogenic variants in the WFS1 gene and manifested by diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Recent genetic and clinical findings have revealed Wolfram syndrome as a spectrum disorder. Therefore, a genotype-phenotype correlation analysis is needed for diagnosis and therapeutic development. Here, we focus on the WFS1 c.1672C>T, p.R558C variant which is highly prevalent in the Ashkenazi-Jewish population. Clinical investigation indicates that subjects carrying the homozygous WFS1 c.1672C>T, p.R558C variant show mild forms of Wolfram syndrome phenotypes. Expression of WFS1 p.R558C is more stable compared to the other known recessive pathogenic variants associated with Wolfram syndrome. Human induced pluripotent stem cell (iPSC)-derived islets (SC-islets) homozygous for WFS1 c.1672C>T variant recapitulate genotype-related Wolfram syndrome phenotypes. Enhancing residual WFS1 function by a combination treatment of chemical chaperones mitigates detrimental effects caused by the WFS1 c.1672C>T, p.R558C variant and increases insulin secretion in SC-islets. Thus, the WFS1 c.1672C>T, p.R558C variant causes a mild form of Wolfram syndrome phenotypes, which can be remitted with a combination treatment of chemical chaperones. We demonstrate that our patient iPSC-derived disease model provides a valuable platform for further genotype-phenotype analysis and therapeutic development for Wolfram syndrome.
2022-09-01 | GSE212256 | GEO
Project description:WFS1 pull-down in HEK293 cells transfected with WFS1 expression plasmid. Precipitated proteins were separates into 13 fractions by SDS-PAGE, digested with trypsin and analyzed by LC-MS/MS. Samples P1-13 = pull-down with anti-WFS rabbit polyclonal (Cell Signaling Technologies #8749S), samples N14-26 = negative control (rabbit IgG).
Mitochondrial dysfunction involving mitochondria-associated ER membrane (MAM) dysregulation is implicated in the pathogenesis of late-onset neurodegenerative
diseases, but understanding is limited for rare early-onset conditions. Loss of the MAMresident
protein WFS1 causes Wolfram syndrome (WS), a rare early-onset
neurodegenerative disease that has been linked to mitochondrial abnormalities. Here
we demonstrated mitochondrial dysfunction in human induced pluripotent stem cellderived
neuronal cells of WS patients. VDAC1 was identified to interact with WFS1,
whereas loss of this interaction in WS cells could compromise mitochondrial function.
Restoring WFS1 levels in WS cells reinstated WFS1-VDAC1 interaction, which
correlated with increase in MAMs and mitochondrial network that could positively affect
mitochondrial function. Genetic rescue by WFS1 overexpression or pharmacological
agents modulating mitochondrial function improved the viability and bioenergetics of
WS neurons. Our data implicate a role of WFS1 in regulating mitochondrial
functionality and highlight a therapeutic intervention for WS and related rare diseases
with mitochondrial defects.
2023-04-05 | MSV000091646 | MassIVE
Project description:Developmental alteration in brain wiring that would make it more susceptible to later pathological processes has been suggested as a basis for the occurrence of neurodegenerative diseases, but mechanisms have remained elusive. A recent series of magnetic resonance imaging studies have demonstrated that, in Wolfram syndrome, neurodegenerative processes appear during childhood and adolescence on top of a clinically silent global defect in brain development. Here, differentiation of induced pluripotent stem cell lines derived from Wolfram syndrome patients’ cells along the neural lineage has revealed phenotypic and molecular correlates of that global brain defect. A proportion of neural cells displayed aberrant neurite outgrowth associated with alterations in the expression of genes involved in axonal guidance. In contrast, an activation of endoplasmic reticulum stress response genes was absent while it is present in late Wolfram syndrome degenerative processes. These results concur to the broader hypothesis that axon guidance genes may play a role in the susceptibility to neurodegenerative diseases.
2021-09-23 | GSE156911 | GEO
Project description:gnp07_regeneome_embryogenesis - embryogenesis ws - Identify genes involved in somatic embryogenesis - To compare embryogenic areas of a callus with undifferenciate area in the same callus
2012-06-01 | GSE30383 | GEO
Project description:Dysregulated neurite outgrowth and synapse formation underlie many psychiatric disorders. Wolfram syndrome (WS) mainly caused by WFS1 deficiency is a monogenic genetic disease manifested by severe psychiatric disorders. Due to athe lack of proper human disease models, the underlying mechanism is poorly understood. Particularly, whether and how WFS1 deficiency affects synapse formation remain elusive. By mirroring the complexity of human brain development with cerebral organoids derived from human embryonic stem cells (hESCs) harboring WFS1 loss of function (LOF), we found that WFS1-deficient cerebral organoids not only recapitulated the neuronal loss phenotype in WS patients, but also exhibited significantly impaired synapse formation associated with reduced astrocytes, suggesting a defective structural basis for psychiatric disorders elicited by WFS1 deficiency. To further unravel the complexity of interplay between neurons and astrocytes, each neural cell type was respectively differentiated from hESCs harboring WFS1 LOF. WFS1 deficiency in neurons autonomously delayed neuronal differentiation with altered expressions of genes associated with psychiatric disorders, and impaired neurite outgrowth and reduced synapse formation associated with elevated cytosolic calcium. Interestingly, WFS1 deficiency in astrocytes decreased the expression of glutamate transporter EAAT2 and compromised glutamate uptake, causing reduced neurite outgrowth with increased cytosolic calcium when co-cultured with wildtype (WT) neurons, highlighting pathogenic role of WFS1-deficient astrocytes. Importantly, restoring EAAT2 expression in astrocytes by riluzole treatment significantly alleviated reduced neurite outgrowth phenotype in WT neurons co-cultured with WFS1-deficient astrocytes. Altogether, our study provides novel insights into how WFS1 deficiency affects neurite outgrowth and synapse formation, potentially contributing to predisposition of psychiatric disorders, and offers a potential strategy of therapy.
2022-03-17 | GSE185052 | GEO