Identification and successful negotiation of a metabolic checkpoint in direct neuronal reprogramming

Gascón, Sergio, Murenu, Elisa, Masserdotti, Giacomo, Ortega, Felipe, Russo, Gianluca L., Petrik, David ORCID: https://orcid.org/0000-0003-3026-0770, Deshpande, Aditi, Heinrich, Christophe, Karow, Marisa, Robertson, Stephen P., Schroeder, Timm, Beckers, Johannes, Irmler, Martin, Berndt, Carsten, Friedmann Angeli, José P., Conrad, Marcus, Berninger, Benedikt and Götz, Magdalena 2016. Identification and successful negotiation of a metabolic checkpoint in direct neuronal reprogramming. Cell Stem Cell 18 (3) , pp. 396-409. 10.1016/j.stem.2015.12.003

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Abstract

Despite the widespread interest in direct neuronal reprogramming, the mechanisms underpinning fate conversion remain largely unknown. Our study revealed a critical time point after which cells either successfully convert into neurons or succumb to cell death. Co-transduction with Bcl-2 greatly improved negotiation of this critical point by faster neuronal differentiation. Surprisingly, mutants with reduced or no affinity for Bax demonstrated that Bcl-2 exerts this effect by an apoptosis-independent mechanism. Consistent with a caspase-independent role, ferroptosis inhibitors potently increased neuronal reprogramming by inhibiting lipid peroxidation occurring during fate conversion. Genome-wide expression analysis confirmed that treatments promoting neuronal reprogramming elicit an anti-oxidative stress response. Importantly, co-expression of Bcl-2 and anti-oxidative treatments leads to an unprecedented improvement in glial-to-neuron conversion after traumatic brain injury in vivo, underscoring the relevance of these pathways in cellular reprograming irrespective of cell type in vitro and in vivo.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	Elsevier
ISSN:	1934-5909
Date of First Compliant Deposit:	11 September 2019
Date of Acceptance:	10 December 2015
Last Modified:	25 Nov 2024 03:15
URI:	https://orca.cardiff.ac.uk/id/eprint/125397

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