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Unfolded protein Response is a major hurdle in direct neuronal reprogramming of human astrocytes

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE248129 | GEO | 2024/01/24

REPOSITORIES: GEO

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Unfolded protein Response is a major hurdle in direct neuronal reprogramming of human astrocytes [Bulk RNA-seq]

Project description: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.

2024-01-24 | GSE248120 | GEO

Unfolded protein Response is a major hurdle in direct neuronal reprogramming of human astrocytes [scRNA-seq day 20]

2024-01-24 | GSE248128 | GEO

Unfolded protein Response is a major hurdle in direct neuronal reprogramming of human astrocytes [scRNA-seq 5 day]

2024-01-24 | GSE248122 | GEO

Direct neuronal reprogramming of NDUFS4 patient cells identifies the unfolded protein response as a novel general reprogramming hurdle.

Project description: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 very little is known about the impact of mitochondrial dysfunction on the direct reprogramming of human cells. Here, we explore the effects of mitochondrial dysfunction on the neuronal reprogramming of induced pluripotent stem cell (iPSC)-derived astrocytes carrying mutations in the NDUFS4 gene, important for Complex I and associated with Leigh syndrome. This led to the identification of the unfolded protein response as a major hurdle in the direct neuronal conversion of not only astrocytes and fibroblasts from patients but also control human astrocytes and fibroblasts. Its transient inhibition potently improves reprogramming by influencing the mitochondria-endoplasmic-reticulum-stress-mediated pathways. Taken together, disease modeling using patient cells unraveled novel general hurdles and ways to overcome these in human astrocyte-to-neuron reprogramming.

| S-EPMC10994141 | biostudies-literature

Unfolded protein Response is a major hurdle in direct neuronal reprogramming of human astrocytes

Project description:Unfolded protein Response is a major hurdle in direct neuronal reprogramming of human astrocytes

| PRJNA1041804 | ENA

Unfolded protein Response is a major hurdle in direct neuronal reprogramming of human astrocytes [Bulk RNA-seq]

Project description:Unfolded protein Response is a major hurdle in direct neuronal reprogramming of human astrocytes [Bulk RNA-seq]

| PRJNA1041800 | ENA

Unfolded protein Response is a major hurdle in direct neuronal reprogramming of human astrocytes [scRNA-seq day 20]

Project description:Unfolded protein Response is a major hurdle in direct neuronal reprogramming of human astrocytes [scRNA-seq day 20]

| PRJNA1041808 | ENA

Unfolded protein Response is a major hurdle in direct neuronal reprogramming of human astrocytes [scRNA-seq 5 day]

Project description:Unfolded protein Response is a major hurdle in direct neuronal reprogramming of human astrocytes [scRNA-seq 5 day]

| PRJNA1041802 | ENA

Multigenerational mistimed feeding drives circadian reprogramming with an impaired unfolded protein response.

Project description:Mistimed food intake in relation to the day/night cycle disrupts the synchrony of circadian rhythms in peripheral tissues and increases the risk of metabolic diseases. However, the health effects over generations have seldom been explored. Here, we established a 10-generation mouse model that was continuously fed with daytime-restricted feeding (DRF). We performed RNA-seq analysis of mouse liver samples obtained every 4 h over a 24 h period from F2, F5 and F10 generations exposed to DRF. Multigenerational DRF programs the diurnal rhythmic transcriptome through a gain or loss of diurnal rhythmicity over generations. Gene ontology (GO) analysis of the differential rhythmic transcriptome revealed that adaptation to persistent DRF is accompanied by impaired endoplasmic reticulum (ER) stress. Consistently, a substantially higher level of folding-deficient proinsulin was observed in F10 liver tissues than in F2 and F5 liver tissues following tail vein injection. Subsequently, tunicamycin induced more hepatocyte death in F10 samples than in F2 and F5 samples. These data demonstrate that mistimed food intake could produce cumulative effects over generations on ER stress sensitivity in mice.

| S-EPMC10025471 | biostudies-literature

Region-Restrict Astrocytes Exhibit Heterogeneous Susceptibility to Neuronal Reprogramming.

Project description:The adult CNS has poor ability to replace degenerated neurons following injury or disease. Recently, direct reprogramming of astrocytes into induced neurons has been proposed as an innovative strategy toward CNS repair. As a cell population that shows high diversity on physiological properties and functions depending on their spatiotemporal distribution, however, whether the astrocyte heterogeneity affect neuronal reprogramming is not clear. Here, we show that astrocytes derived from cortex, cerebellum, and spinal cord exhibit biological heterogeneity and possess distinct susceptibility to transcription factor-induced neuronal reprogramming. The heterogeneous expression level of NOTCH1 signaling in the different CNS regions-derived astrocytes is shown to be responsible for the neuronal reprogramming diversity. Taken together, our findings demonstrate that region-restricted astrocytes reveal different intrinsic limitation of the response to neuronal reprogramming.

| S-EPMC6373495 | biostudies-literature

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