NGLY1 mutations cause protein aggregation in human neurons
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA810420 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18140148_1.fastq.gz | Fastqsanger.gz | |||
| SRR18140148_2.fastq.gz | Fastqsanger.gz | |||
| SRR18140149_1.fastq.gz | Fastqsanger.gz | |||
| SRR18140149_2.fastq.gz | Fastqsanger.gz | |||
| SRR18140150_1.fastq.gz | Fastqsanger.gz |
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Project description:Biallelic mutations in the gene that encodes the enzyme N-glycanase 1 (NGLY1) cause a rare disease with multi-symptomatic features including developmental delay, intellectual disability, neuropathy and seizures. NGLY1’s activity in human neural cells is currently not well understood. To understand how NGLY1 gene loss leads to the specific phenotypes of NGLY1 deficiency, we employed direct conversion of NGLY1 patient-derived induced pluripotent stem cells (iPSCs) to functional cortical neurons. Transcriptomic, proteomic, and functional studies of iPSC-derived neurons lacking NGLY1 function revealed several major cellular processes that were altered, including protein aggregate-clearing functionality, mitochondrial homeostasis, and synaptic dysfunctions. These phenotypes were rescued by introduction of a functional NGLY1 gene and were observed in iPSC-derived mature neurons, but not astrocytes. Finally, laser capture microscopy followed by mass spectrometry provided detailed characterization of the composition of protein aggregates specific to NGLY1-deficient neurons. Future studies will harness this knowledge for therapeutic development.
2025-02-13 | GSE197454 | GEO
Project description:Biallelic mutations in the gene that encodes the enzyme N-glycanase 1 (NGLY1) cause a rare disease with multi-symptomatic features including developmental delay, intellectual disability, neuropathy and seizures. NGLY1’s activity in human neural cells is currently not well understood. To understand how NGLY1 gene loss leads to the specific phenotypes of NGLY1 deficiency, we employed direct conversion of NGLY1 patient-derived induced pluripotent stem cells (iPSCs) to functional cortical neurons. Transcriptomic, proteomic, and functional studies of iPSC-derived neurons lacking NGLY1 function revealed several major cellular processes that were altered, including protein aggregate-clearing functionality, mitochondrial homeostasis, and synaptic dysfunctions. These phenotypes were rescued by introduction of a functional NGLY1 gene and were observed in iPSC-derived mature neurons, but not astrocytes. Finally, laser capture microscopy followed by mass spectrometry provided detailed characterization of the composition of protein aggregates specific to NGLY1-deficient neurons. Future studies will harness this knowledge for therapeutic development.
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Project description:NGlY1 deficiency is an ultra-rare, autosomal recessive genetic disease caused by mutations in the NGLY1 gene encoding N-glycanase one that removes N-linked glycan. Patients with pathogenic mutations in NGLY1 have complex clinical symptoms including global developmental delay, motor disorder, and liver dysfunction. To better understand disease pathogensis and neurological symptoms of NGLY1 deficiency we generated and characterized midbrain organoids using patient-derived iPSCs from two patients with disease causing mutations.
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Project description:We report using a single-cell transcriptomic study of cerebral organiods (COs) developed from WA09 hESCs with gene editing-induced NGLY1 mutations and from NGLY1-deficient patient's hiPSCs at 40 or 80 days of development. WA09 hESC-derived COs with and without mutant NGLY1 and patient's hiPSC-derived COs with and without the ectopic expression NGLY1 were analyzed.
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Project description:The data includes a transcriptome analysis of K562 cell lines in which the gene N-glycanase 1 (NGLY1) was mutated in exon 1 and/or exon 3 to include loss of function mutations as described in Mueller and Jakob et al, 2020. The data were used in conjunction with whole proteome MS/MS experiments to show a gene expression profile consistent with NGLY1 deficiency, a human disease. The experiments demonstrate the wide ranging effect of the loss of NGLY1 on a cellular system.
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Project description:Although NGLY1 deficiency has been discovered as a result of mutations in the NGLY1 gene, cellular and molecular mechanisms underlying the neurological abnormalities due to NGLY1 malfunction in the brain remain mostly unknown. Using human cerebral organoid (CO) models and systems biology techniques, we uncovered NGLY1 deficiencyinduced alterations at the early stage of cerebral development. Despite the similar vitality and cellular pluripotency of NGLY1-functional and -deficient WA09 hESCs, COs developed from the NGLY1-deficient hESCs had the defective formation of SATB2+ upper-layer neurons and attenuation of STAT3 and HES1 signaling critical for sustaining radial glia. The NGLY1-deficient CO cells, compared with the NGLY1-functional ones, also presented higher vulnerability to multiple stressors. Bulk and single-cell analysis of transcriptomes revealed that NGLY1-deficient COs showed a propensity for premature neuronal differentiation, accompanied by significant downregulation of secretory and transcription factors, including TTR, IGFBP2, and ID4. Supplementing recombinant TTR to NGLY1-deficient CO cells reduced their susceptibility to proteasome inhibition. Ectopic expression of NGLY1 led to IGFBP2 and ID4 upregulation in CO cells developed from NGLY-deficient patientderived induced pluripotent stem cells (iPSCs). Moreover, ID4 expression, STAT3 signaling, and proliferation were enhanced by treatment of recombinant IGFBP2 in CO cells developed from the NGLY1-deficient WA09 hESCs and patient-derived iPSCs. Our findings indicate that NGLY1 could be critical for regulating various stress responses and maintaining neural stem cells (NSCs) in the developing cerebrum. In patients, NGLY1 deficiencyassociated neurological abnormalities, including microcephaly, may be a consequence of aberrations in NSC signaling sustained by NGLY1.
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Project description:Analysis of human cerebral organoids developed from both WA09 human embryonic stem cells with CRISPR-KO of NGLY1. The hypothesis tested was that NGLY1 is key to normal human brain development and when knocked out would alter cerebral development of organoids through the differential expression of various key genes.
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Project description:Heterozygous loss-of-function mutations in the synaptic scaffolding gene SHANK2 are strongly associated with autism spectrum disorder (ASD). To investigate their effect on synaptic connectivity, we generated cortical neurons from induced pluripotent stem cells (iPSC) derived from neurotypic and ASD-affected donors. We developed Sparse coculture for Connectivity (SparCon) assays where SHANK2 and control neurons were differentially labeled and sparsely seeded together on a lawn of unlabeled control neurons. We observed striking increases in total synapse number and dendrite complexity. Dendrite length increases were exacerbated by IGF1 or BDNF treatment. Increased excitatory synapse function in haploinsufficient SHANK2 neurons was phenocopied in gene-edited knockout SHANK2 neurons. Gene correction of an ASD SHANK2 mutation rescued excitatory synapse function supporting a role for SHANK2 as a negative regulator of connectivity in developing human neurons. The transcriptome in these isogenic SHANK2 neurons was deeply perturbed in synaptic and plasticity gene sets and ASD gene modules, and activity dependent dendrite extension was defective. Our unexpected findings provide evidence for hyperconnectivity and profoundly altered transcriptome in SHANK2 neurons derived from ASD subjects.
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