Apoptosis signaling is activated as a transient pulse in neurons

ABSTRACT Apoptosis is a fundamental process of all mammalian cells but exactly how it is regulated in different primary cells remains less explored. In most contexts, apoptosis is engaged to

eliminate cells. However, postmitotic cells such as neurons must efficiently balance the need for developmental apoptosis _versus_ the physiological needs for their long-term survival.

Neurons are capable of reversing the commitment to death even after the point of cytochrome _c_ release. This ability of neurons to recover from an apoptotic signal suggests that activation

of the apoptotic pathway in neurons could be much more transient than is currently recognized. Here, we investigated whether the apoptotic pathway in neurons is a persistent signal or a

transient pulse in continuous presence of apoptotic stimulus. We have examined this at three key steps in apoptotic signaling: phosphorylation of c-Jun, induction of the BH3-only family

proteins and Bax activation. Strikingly, we found all three of these events occur as transient signals following Nerve Growth Factor (NGF) deprivation-induced apoptosis in sympathetic

neurons. This transient apoptosis signal would effectively allow neurons to reset and permit recovery if the apoptotic stimulus is reversed. Excitingly, we have also discovered that a

neuron’s ability to recover from an apoptotic signal is dependent on expression of the anti-apoptotic Bcl-2 family protein Bcl-xL. Bcl-xL-deficient neurons lose the ability to recover from

NGF deprivation even if NGF is restored. Additionally, we show that recovery from a previous exposure to NGF deprivation is protective against subsequent deprivation. Together, these results

define a novel mechanism by which apoptosis is regulated in neurons where the transient pulse of the apoptotic signaling supports neuronal resilience. Access through your institution Buy or

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DIVERSE MATURITY-DEPENDENT AND COMPLEMENTARY ANTI-APOPTOTIC BRAKES SAFEGUARD HUMAN IPSC-DERIVED NEURONS FROM CELL DEATH Article Open access 21 October 2022 SURVIVAL OF COMPROMISED ADULT

SENSORY NEURONS INVOLVES MACROVESICULAR FORMATION Article Open access 24 November 2022 STRESSED NEURONAL CELLS CAN RECOVER FROM PROFOUND MEMBRANE BLEBBING, NUCLEAR CONDENSATION AND

MITOCHONDRIAL FRAGMENTATION, BUT NOT FROM CYTOCHROME C RELEASE Article Open access 08 July 2023 DATA AVAILABILITY Because no large datasets were generated or analyzed in this current study,

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genome repair sites in postmitotic human neurons. Science. 2021;372:91–4. Article  PubMed  PubMed Central  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS We thank the Deshmukh lab

members for their critical review of this manuscript and contribution to discussions of this work. FUNDING Funding was supported by NIH grants GM118331 and AG082140 to MD. AUTHOR

INFORMATION AUTHORS AND AFFILIATIONS * Neuroscience Center; University of North Carolina, Chapel Hill, NC, USA Keeley L. Spiess, Elizabeth S. Hammond, Rachel L. Patterson & Mohanish

Deshmukh * Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, USA Matthew J. Geden, Selena E. Romero, Emilie Hollville, Quintin B. Girardi & 

Mohanish Deshmukh Authors * Keeley L. Spiess View author publications You can also search for this author inPubMed Google Scholar * Matthew J. Geden View author publications You can also

search for this author inPubMed Google Scholar * Selena E. Romero View author publications You can also search for this author inPubMed Google Scholar * Emilie Hollville View author

publications You can also search for this author inPubMed Google Scholar * Elizabeth S. Hammond View author publications You can also search for this author inPubMed Google Scholar * Rachel

L. Patterson View author publications You can also search for this author inPubMed Google Scholar * Quintin B. Girardi View author publications You can also search for this author inPubMed 

Google Scholar * Mohanish Deshmukh View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS KLS contributed conception, design, data collection and

analysis, interpretation, and manuscript writing. MJG and SER performed experiments with Bcl-xL neurons treated with AAV in Fig. 4 and assisted with conception and experiment design. ESH and

RLP performed dissections and immunofluorescence. QBG performed immunofluorescence, imaging and image analysis in Fig. 3. EH performed qPCR analysis. MD contributed conception, design,

financial support and manuscript writing. CORRESPONDING AUTHOR Correspondence to Mohanish Deshmukh. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. ETHICS

This work does not include any human subjects. All mouse work was completed in compliance with IACUC standards, and all protocols were approved. ADDITIONAL INFORMATION PUBLISHER’S NOTE

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WHOLE WESTERN BLOT OF MKP1 SUPPLEMENTARY FIGURE 1 LEGEND WHOLE BAX WESTERN BLOT RELATED TO FIGURE 2. RIGHTS AND PERMISSIONS Springer Nature or its licensor (e.g. a society or other partner)

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solely governed by the terms of such publishing agreement and applicable law. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Spiess, K.L., Geden, M.J., Romero, S.E. _et al._

Apoptosis signaling is activated as a transient pulse in neurons. _Cell Death Differ_ 32, 521–529 (2025). https://doi.org/10.1038/s41418-024-01403-5 Download citation * Received: 08 May 2024

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