Identification and Successful Negotiation of a Metabolic Checkpoint in Direct Neuronal Reprogramming

Sergio Gascón; Elisa Murenu; Giacomo Masserdotti; Felipe Ortega; Gianluca L. Russo; David Petrik; Aditi Deshpande; Christophe Heinrich; Marisa Karow; Stephen P. Robertson; Timm Schroeder; Johannes Beckers; Martin Irmler; Carsten Berndt; José P.Friedmann Angeli; Marcus Conrad; Benedikt Berninger; Magdalena Götz

doi:10.1016/j.stem.2015.12.003

Identification and Successful Negotiation of a Metabolic Checkpoint in Direct Neuronal Reprogramming

Sergio Gascón, Elisa Murenu, Giacomo Masserdotti, Felipe Ortega, Gianluca L. Russo, David Petrik, Aditi Deshpande, Christophe Heinrich, Marisa Karow, Stephen P. Robertson, Timm Schroeder, Johannes Beckers, Martin Irmler, Carsten Berndt, José P.Friedmann Angeli, Marcus Conrad, Benedikt Berninger, Magdalena Götz^*

^*Corresponding author for this work

Developmental Neurobiology

Research output: Contribution to journal › Article › peer-review

292 Citations (Scopus)

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.

Original language	English
Pages (from-to)	396-409
Number of pages	14
Journal	Cell Stem Cell
Volume	18
Issue number	3
Early online date	31 Dec 2015
DOIs	https://doi.org/10.1016/j.stem.2015.12.003
Publication status	Published - 3 Mar 2016

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Gascón, S., Murenu, E., Masserdotti, G., Ortega, F., Russo, G. L., Petrik, D., Deshpande, A., Heinrich, C., Karow, M., Robertson, S. P., Schroeder, T., Beckers, J., Irmler, M., Berndt, C., Angeli, J. P. F., Conrad, M., Berninger, B., & Götz, M. (2016). Identification and Successful Negotiation of a Metabolic Checkpoint in Direct Neuronal Reprogramming. Cell Stem Cell, 18(3), 396-409. https://doi.org/10.1016/j.stem.2015.12.003

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title = "Identification and Successful Negotiation of a Metabolic Checkpoint in Direct Neuronal Reprogramming",

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.",

author = "Sergio Gasc{\'o}n and Elisa Murenu and Giacomo Masserdotti and Felipe Ortega and Russo, {Gianluca L.} and David Petrik and Aditi Deshpande and Christophe Heinrich and Marisa Karow and Robertson, {Stephen P.} and Timm Schroeder and Johannes Beckers and Martin Irmler and Carsten Berndt and Angeli, {Jos{\'e} P.Friedmann} and Marcus Conrad and Benedikt Berninger and Magdalena G{\"o}tz",

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Gascón, S, Murenu, E, Masserdotti, G, Ortega, F, Russo, GL, Petrik, D, Deshpande, A, Heinrich, C, Karow, M, Robertson, SP, Schroeder, T, Beckers, J, Irmler, M, Berndt, C, Angeli, JPF, Conrad, M, Berninger, B & Götz, M 2016, 'Identification and Successful Negotiation of a Metabolic Checkpoint in Direct Neuronal Reprogramming', Cell Stem Cell, vol. 18, no. 3, pp. 396-409. https://doi.org/10.1016/j.stem.2015.12.003

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AU - Murenu, Elisa

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AU - Russo, Gianluca L.

AU - Petrik, David

AU - Deshpande, Aditi

AU - Heinrich, Christophe

AU - Karow, Marisa

AU - Robertson, Stephen P.

AU - Schroeder, Timm

AU - Beckers, Johannes

AU - Irmler, Martin

AU - Berndt, Carsten

AU - Angeli, José P.Friedmann

AU - Conrad, Marcus

AU - Berninger, Benedikt

AU - Götz, Magdalena

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AB - 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.

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Identification and Successful Negotiation of a Metabolic Checkpoint in Direct Neuronal Reprogramming

Abstract

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