Direct neuronal reprogramming of NDUFS4 patient cells identifies the unfolded protein response as a novel general reprogramming hurdle
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Mitochondria account for essential cellular pathways, from ATP production to nucleotide metabolism, and their deficits lead to neurological disorders and contribute to the onset of age-related diseases. Direct neuronal reprogramming aims at replacing neurons lost in such conditions, but almost nothing is known about the impact of mitochondrial dysfunction in human cell direct reprogramming. Here we explore the defects and how to improve the neuronal reprogramming of iPSC-derived astrocytes carrying mutations in NDUFS4 gene, important for Complex I and associated to Leigh Sydrome. This led to the identification of the unfolded protein response as a major hurdle in the direct neuronal conversion of not only patient, but also control astrocytes and fibroblasts. Our data highlight mitochondria-ER stress-mediated inhibition of translation as a key hurdle in direct neuronal reprogramming, emphasizing how disease modelling using patient cells can contribute to unravel novel pathways in human glia cell reprogramming.
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Created: 8th Jul 2024 at 10:50
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Projects: SyNergy - published datasets
Institutions: Helmholtz Munich, LMU
Projects: SyNergy - published datasets
Institutions: Klinikum der Universität München
Public web page: Not specified
Organisms: Mus musculus, Rattus norvegicus, Homo sapiens, Macaca mulatta, Sus scrofa
Submitter: Rainer Malik
Studies: A genome-wide in vivo CRISPR screen identifies essential regulators of T..., Correlation spatial transcriptomics/EM, Direct neuronal reprogramming of NDUFS4 patient cells identifies the unf..., Early adaptive immune activation detected in monozygotic twins with prod..., Histone Deacetylase 9 Activates IKK to Regulate Atherosclerotic Plaque V..., Innate immune memory after brain injury drives inflammatory cardiac dysf..., Microglia in white matter aging, Myelin degeneration in leucodystrophies, Oligodendrocytes in AD models, Oligodendrocytes in white matter aging, Phagocyte-mediated synapse removal in cortical neuroinflammation is prom..., Skin and gut imprinted helper T cell subsets exhibit distinct functional..., T cells modulate the microglial response to brain ischemia
Assays: Bulk RNA-seq, Expression profiling by high throughput sequencing, Expression profiling by high throughput sequencing, Expression profiling by high throughput sequencing, Expression profiling by high throughput sequencing, Expression profiling by high throughput sequencing, Expression profiling by high throughput sequencing, Expression profiling by high throughput sequencing, Expression profiling by high throughput sequencing, Expression profiling by high throughput sequencing, Expression profiling by high throughput sequencing, Single cell RNA sequencing experiment, scRNA-seq 5 day, scRNA-seq day 20
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human IPSCs from control or patients with NDUFS4 mutations were differentiated into proliferating and non-proliferating astrocytes. Three control and 3 patients lines were analyzed. Per each line, 3 biological replicates were collected at 3 stages: IPSC, proliferating astrocyte and non-proliferating astrocytes.
Submitter: Rainer Malik
Assay type: Experimental Assay Type
Technology type: Technology Type
Investigation: Transcriptomics
Organisms: No organisms
SOPs: No SOPs
Data files: Unfolded protein Response is a major hurdle in ...
Snapshots: No snapshots
pAstros were transduced with control or Ngn2-expressing retrovirus. 2DPT, media was replaced with differentiation media in absence of presence of AMG; 5DPT, DsRed-positive cells were sorted, barcoded with CMOs and analyzed by scRNAseq via 10XGenoics platform
Submitter: Rainer Malik
Assay type: Experimental Assay Type
Technology type: Technology Type
Investigation: Transcriptomics
Organisms: Homo sapiens
SOPs: No SOPs
Data files: Unfolded protein Response is a major hurdle in ...
Snapshots: No snapshots
pAstros were transduced with control or Ngn2-expressing retrovirus. 2DPT, media was replaced with differentiation media in absence of presence of AMG; 20DPT, DsRed-positive cells were sorted, barcoded with CMOs and analyzed by scRNAseq via 10XGenoics platform
Submitter: Rainer Malik
Assay type: Experimental Assay Type
Technology type: Technology Type
Investigation: Transcriptomics
Organisms: Homo sapiens
SOPs: No SOPs
Data files: Unfolded protein Response is a major hurdle in ...
Snapshots: No snapshots
Mitochondria account for essential cellular pathways, from ATP production to nucleotide metabolism, and their deficits lead to neurological disorders and contribute to the onset of age-related diseases. Direct neuronal reprogramming aims at replacing neurons lost in such conditions, but almost nothing is known about the impact of mitochondrial dysfunction in human cell direct reprogramming. Here we explore the defects and how to improve the neuronal reprogramming of iPSC-derived astrocytes carrying ...
Creators: Rainer Malik, Magdalena Götz
Submitter: Rainer Malik
Investigations: Transcriptomics
Studies: Direct neuronal reprogramming of NDUFS4 patient...
Assays: scRNA-seq day 20
Mitochondria account for essential cellular pathways, from ATP production to nucleotide metabolism, and their deficits lead to neurological disorders and contribute to the onset of age-related diseases. Direct neuronal reprogramming aims at replacing neurons lost in such conditions, but almost nothing is known about the impact of mitochondrial dysfunction in human cell direct reprogramming. Here we explore the defects and how to improve the neuronal reprogramming of iPSC-derived astrocytes carrying ...
Creators: Rainer Malik, Magdalena Götz
Submitter: Rainer Malik
Investigations: Transcriptomics
Studies: Direct neuronal reprogramming of NDUFS4 patient...
Assays: scRNA-seq 5 day
Mitochondria account for essential cellular pathways, from ATP production to nucleotide metabolism, and their deficits lead to neurological disorders and contribute to the onset of age-related diseases. Direct neuronal reprogramming aims at replacing neurons lost in such conditions, but almost nothing is known about the impact of mitochondrial dysfunction in human cell direct reprogramming. Here we explore the defects and how to improve the neuronal reprogramming of iPSC-derived astrocytes carrying ...
Creators: Rainer Malik, Magdalena Götz
Submitter: Rainer Malik
Investigations: Transcriptomics
Studies: Direct neuronal reprogramming of NDUFS4 patient...
Assays: Bulk RNA-seq