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 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.
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Created: 4th Aug 2026 at 11:25
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https://orcid.org/0000-0003-1551-9203
Projects: CRC1002: Modulatory Units in Heart Failure, TRR 274: Checkpoints of Central Nervous System Recovery, SFB 1190: Compartmental Gates and Contact Sites in Cells
Web page: Not specified
https://rdp.sfb274.de/ (Research Data Platform) https://gepris.dfg.de/gepris/projekt/408885537 (DFG Gepris entry) The central nervous system (CNS) is a terminally differentiated tissue, where any insult carries a heightened risk - yet the tissue response to these insults is variable and can range from irreversible destruction to almost complete recovery. The rules that instruct these divergent outcomes are still unknown. The aim of this CRC is therefore to understand the biology of the multicellular ...
Programme: Sonderforschungsbereiche/Collaborative Research Centers
Public web page: https://www.sfb274.de/
Neuronal loss in acute or chronic brain disease could be treated by neuronal replacement strategies, such as transplantation of young neurons, if they integrate properly into the existing networks. Here we explore the cell-based and molecular mechanisms causing hyperinnervation and overshoot loss of input connectivity as well as the newly discovered hurdle in output connectivity, the lack of myelination. Candidate as well as unbiased approaches are pursued to identify the critical checkpoints and ...
Submitter: Camilla Giudici
Studies: Astrocyte heterogeneity reveals region-specific astrogenesis in the whit..., Brain injury environment critically influences the connectivity of trans..., Direct neuronal reprogramming of NDUFS4 patient cells identifies the unf..., Direct neuronal reprogramming of mouse astrocytes is associated with mul..., Heterogeneity of neurons reprogrammed from spinal cord astrocytes by the..., Injury-specific factors in the cerebrospinal fluid regulate astrocyte pl..., Single Cell Deletion of the Transcription Factors Trps1 and Sox9 in Astr...
Assays: Expression profiling, Expression profiling by array, Expression profiling: Bulk RNA-seq (human), Expression profiling: Bulk RNA-seq (mouse), Expression profiling: Single-cell multiome (scRNA-seq + scATAC-seq), Bul..., Expression profiling: Spatial Transcriptomics (mouse), Expression profiling: Spatial Transcriptomics (mouse), Expression profiling: scRNA-seq (human) (Day 20), Expression profiling: scRNA-seq (human) (Day 5), Expression profiling: scRNA-seq (mouse), Expression profiling: scRNA-seq (mouse), Expression profiling: scRNA-seq (mouse), Shotgun proteomics (human), Shotgun proteomics (mouse), scRNA-seq and scATAC-seq
Submitter: Camilla Giudici
Assay type: Transcriptomics
Technology type: Sequencing
Investigation: C05 - Glial checkpoints for neuronal circuitry ...
Submitter: Camilla Giudici
Assay type: Transcriptomics
Technology type: Sequencing
Investigation: C05 - Glial checkpoints for neuronal circuitry ...
Submitter: Camilla Giudici
Assay type: Transcriptomics
Technology type: Sequencing
Investigation: C05 - Glial checkpoints for neuronal circuitry ...
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 10XGenomics platform.
Creators: None
Submitter: Camilla Giudici
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 10XGenomics platform
Creators: None
Submitter: Camilla Giudici
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.
Creators: None
Submitter: Camilla Giudici
Abstract
Authors: Giovanna Sonsalla, Ana Belen Malpartida, Therese Riedemann, Mirjana Gusic, Ejona Rusha, Giorgia Bulli, Sonia Najas, Aleks Janjic, Bob A. Hersbach, Pawel Smialowski, Micha Drukker, Wolfgang Enard, Jochen H.M. Prehn, Holger Prokisch, Magdalena Götz, Giacomo Masserdotti
Date Published: 1st Apr 2024
Publication Type: Journal Article
