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Sonsalla, G. ; Malpartida, A.B. ; Riedemann, T.* ; Gusic, M. ; Rusha, E. ; Bulli, G. ; Najas, S. ; Janjic, A.* ; Hersbach, B.A. ; Smialowski, P. ; Drukker, M. ; Enard, W.* ; Prehn, J.H.M.* ; Prokisch, H. ; Götz, M. ; Masserdotti, G.

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

Neuron 112, 1117-1132.e9 (2024)

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	Open Access Gold (Paid Option)

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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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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Leigh Syndrome ; Astrocytes ; Direct Neuronal Reprogramming ; Mitochondria ; Unfolded Protein Response; Complex-i; Endoplasmic-reticulum; Nicotinamide Riboside; Er Stress; Rna-seq; Subunit; Fate; Differentiation; Heterogeneity; Mitochondria

ISSN (print) / ISBN 0896-6273

e-ISSN 1097-4199

Journal Neuron

Quellenangaben Volume: 112, Issue: 7, Pages: 1117-1132.e9

Publisher Cell Press

Publishing Place Cambridge, Mass.

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Stem Cell Research (ISF)
Institute of Neurogenomics (ING)

Grants
New Frontiers in Research Fund Transformation grant
CIHR
NSERC
SSHRC
ERC
European Union
German Research Foundation