A deep phenotyping study in mouse and iPSC models to understand the role of oligodendroglia in optic neuropathy in Wolfram syndrome
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ABSTRACT:
PROVIDER: PRJNA1101498 | ENA |
REPOSITORIES: ENA
Dataset's files
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| 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 |
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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: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:Glaucoma is an optic neuropathy characterized by progressive degeneration of retinal ganglion cells (RGCs) and visual loss. Previous studies have reported that the variation of the ATP-binding cassette transporter 1 (ABCA1) gene is linked to a higher risk of glaucoma in humans, but the pathological mechanisms remain unknown. Here we report that ABCA1 loss, especially in astrocytes, causes optic neuropathy. ABCA1 was mainly expressed in astrocytes rather than neurons, and that knockout of Abca1 gene under GFAP promoter (Glia-KO) caused age-associated RGC degeneration and ocular dysfunction without affecting intraocular pressure, a major risk factor for glaucoma. Glia-KO mice showed age-associated changes in astrocyte reactivity accompanied by the accumulation of cholesterol, a major substrate of ABCA1. Single-cell RNA sequencing revealed that Abca1 deficiency causes astrocyte-triggered inflammation and increased sensitivity of RGCs against excitotoxicity. Altogether, these findings suggest that astrocytic dysfunction caused by ABCA1 loss triggers age-associated optic neuropathy-like pathology.
2022-07-11 | GSE207929 | GEO
Project description:Glaucoma is an optic neuropathy characterized by progressive degeneration of retinal ganglion cells (RGCs) and visual loss. Previous studies have reported that the variation of the ATP-binding cassette transporter 1 (ABCA1) gene is linked to a higher risk of glaucoma in humans, but the pathological mechanisms remain unknown. Here we report that ABCA1 loss, especially in astrocytes, causes optic neuropathy. ABCA1 was mainly expressed in astrocytes rather than neurons, and that knockout of Abca1 gene under GFAP promoter (Glia-KO) caused age-associated RGC degeneration and ocular dysfunction without affecting intraocular pressure, a major risk factor for glaucoma. Glia-KO mice showed age-associated changes in astrocyte reactivity accompanied by the accumulation of cholesterol, a major substrate of ABCA1. Single-cell RNA sequencing revealed that Abca1 deficiency causes astrocyte-triggered inflammation and increased sensitivity of RGCs against excitotoxicity. Altogether, these findings suggest that astrocytic dysfunction caused by ABCA1 loss triggers age-associated optic neuropathy-like pathology.
2022-07-11 | GSE207928 | GEO
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:BackgroundWolfram Syndrome type 2 (WFS2) is considered a phenotypic and genotypic variant of WFS, whose minimal criteria for diagnosis are diabetes mellitus and optic atrophy. The disease gene for WFS2 is CISD2. The clinical phenotype of WFS2 differs from WFS1 for the absence of diabetes insipidus and psychiatric disorders, and for the presence of bleeding upper intestinal ulcers and defective platelet aggregation. After the first report of consanguineous Jordanian patients, no further cases of WFS2 have been reported worldwide. We describe the first Caucasian patient affected by WFS2.Case presentationThe proband was a 17 year-old girl. She presented diabetes mellitus, optic neuropathy, intestinal ulcers, sensorineural hearing loss, and defective platelet aggregation to ADP. Genetic testing showed a novel homozygous intragenic deletion of CISD2 in the proband. Her brother and parents carried the heterozygous mutation and were apparently healthy, although they showed subclinical defective platelet aggregation. Long runs of homozygosity analysis from SNP-array data did not show any degree of parental relationship, but the microsatellite analysis confirmed the hypothesis of a common ancestor.ConclusionOur patient does not show optic atrophy, one of the main diagnostic criteria for WFS, but optic neuropathy. Since the "asymptomatic" optic atrophy described in Jordanian patients is not completely supported, we could suppose that the ocular pathology in Jordanian patients was probably optic neuropathy and not optic atrophy. Therefore, as optic atrophy is required as main diagnostic criteria of WFS, it might be that the so-called WFS2 could not be a subtype of WFS. In addition, we found an impaired aggregation to ADP and not to collagen as previously reported, thus it is possible that different experimental conditions or inter-patient variability can explain different results in platelet aggregation. Further clinical reports are necessary to better define the clinical spectrum of this syndrome and to re-evaluate its classification.
| S-EPMC4121299 | biostudies-literature
Project description:Astrocytic dysfunction induced by ABCA1 deficiency causes optic neuropathy
| PRJNA857697 | ENA
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:We revealed transcriptome differences between corrected and unedited (diseased) Wolfram Syndrome patient stem cell-derived beta cells. We also identified several endocrine, pancreatic, and non-pancreatic cell types in the samples populations.
2020-04-22 | GSE139535 | GEO
Project description:MCT1-dependent energetic failure and neuroinflammation underlie optic nerve degeneration in Wolfram syndrome mice
| PRJNA849417 | ENA