CED-4 CARD domain residues can modulate non-apoptotic neuronal regeneration functions independently from apoptosis

Wang, Guoqiang; Sun, Lin; Reina, Christopher P.; Song, Isaac; Gabel, Christopher V.; Driscoll, Monica

doi:10.1038/s41598-019-49633-9

Cited by 7 publications

(6 citation statements)

References 35 publications

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“…It is noteworthy that CED-4 and its mammalian Apaf1 relatives regulate a variety of cellular functions that are unrelated to their activities in PCD. These include cell growth control influenced by DNA damage, centrosomal function and morphology, neuronal regeneration, and inhibition of viral replication ( Zermati et al, 2007 ; Ferraro et al, 2011 ; Liu et al, 2006 ; Wang et al, 2019 ). In addition, as a result of differential RNA splicing, ced-4 encodes proteins with opposing activities, generating both an activator and a repressor of apoptosis ( Chaudhary et al, 1998 ), which further complicates analysis of its action.…”

Section: Discussionmentioning

confidence: 99%

Regulation of defective mitochondrial DNA accumulation and transmission in C. elegans by the programmed cell death and aging pathways

Flowers,

Kothari,

Torres Cleuren

et al. 2023

eLife

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The heteroplasmic state of eukaryotic cells allows for cryptic accumulation of defective mitochondrial genomes (mtDNA). ‘Purifying selection’ mechanisms operate to remove such dysfunctional mtDNAs. We found that activators of programmed cell death (PCD), including the CED-3 and CSP-1 caspases, the BH3-only protein CED-13, and PCD corpse engulfment factors, are required in C. elegans to attenuate germline abundance of a 3.1-kb mtDNA deletion mutation, uaDf5, which is normally stably maintained in heteroplasmy with wildtype mtDNA. In contrast, removal of CED-4/Apaf1 or a mutation in the CED-4-interacting prodomain of CED-3, do not increase accumulation of the defective mtDNA, suggesting induction of a non-canonical germline PCD mechanism or non-apoptotic action of the CED-13/caspase axis. We also found that the abundance of germline mtDNAuaDf5 reproducibly increases with age of the mothers. This effect is transmitted to the offspring of mothers, with only partial intergenerational removal of the defective mtDNA. In mutants with elevated mtDNAuaDf5 levels, this removal is enhanced in older mothers, suggesting an age-dependent mechanism of mtDNA quality control. Indeed, we found that both steady-state and age-dependent accumulation rates of uaDf5 are markedly decreased in long-lived, and increased in short-lived, mutants. These findings reveal that regulators of both PCD and the aging program are required for germline mtDNA quality control and its intergenerational transmission.

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Section: Discussionmentioning

confidence: 99%

Regulation of defective mitochondrial DNA accumulation and transmission in C. elegans by the programmed cell death and aging pathways

Flowers,

Kothari,

Torres Cleuren

et al. 2023

eLife

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show abstract

“…This process is partially reliant upon calcium-mediated CED-4/Apaf-1 signaling. CED-4/Apaf-1 is a key mediator of the conserved apoptotic caspase pathway which contributes to the removal of presynaptic domains in C. elegans ( Meng et al, 2015 ; Miller-Fleming et al, 2016 ), synapse elimination in higher order species ( Ertürk et al, 2014 ; Wang et al, 2014 ; Li et al, 2010 ), and more substantial neuronal remodeling, such as regeneration following injury ( Pinan-Lucarre et al, 2012 ; Wang et al, 2019 ). We find that suppression of the caspase activator CED-4 reduces age-associated decline in neuron dynamics in a manner comparable to that of unc-2 lf mutation and opposite that of the unc-2 gfmutation ( Figure 6 ).…”

Section: Discussionmentioning

confidence: 99%

Age-associated changes to neuronal dynamics involve a disruption of excitatory/inhibitory balance in C. elegans

Wirak

Florman

Alkema

et al. 2022

eLife

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In the aging brain, many of the alterations underlying cognitive and behavioral decline remain opaque. C. elegans offers a powerful model for aging research, with a simple, well-studied nervous system to further our understanding of the cellular modifications and functional alterations accompanying senescence. We perform multi-neuronal functional imaging across the aged C. elegans nervous system, measuring an age-associated breakdown in system-wide functional organization. At single-cell resolution, we detect shifts in activity dynamics toward higher frequencies. In addition, we measure a specific loss of inhibitory signaling that occurs early in the aging process and alters the systems critical excitatory/inhibitory balance. These effects are recapitulated with mutation of the calcium channel subunit UNC-2/CaV2a. We find that manipulation of inhibitory GABA signaling can partially ameliorate or accelerate the effects of aging. The effects of aging are also partially mitigated by disruption of the insulin signaling pathway, known to increase longevity, or by a reduction of caspase activation. Data from mammals are consistent with our findings, suggesting a conserved shift in the balance of excitatory/inhibitory signaling with age that leads to breakdown in global neuronal dynamics and functional decline.

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“…CED-3/caspase activity is necessary and ced-3/caspase acts in the damaged neuron ( Figure 4B ). CED-4/Apaf-1 also promotes regeneration with a subdomain of the caspase recruitment domain (CARD) of CED-4/Apaf-1 regulating CED-3/caspase ( Wang et al, 2019 ). While CED-3/caspase and CED-4/Apaf-1 are involved in initial outgrowth and rapid reconnection, they are not essential for growth per se: loss of these genes does not affect regeneration long term.…”

Section: Non-canonical Roles Of Apoptotic Genes In the Nematode Nervo...mentioning

confidence: 99%

Repurposing the Killing Machine: Non-canonical Roles of the Cell Death Apparatus in Caenorhabditis elegans Neurons

Juanez

Ghose

2022

Front. Cell Dev. Biol.

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Here we highlight the increasingly divergent functions of the Caenorhabditis elegans cell elimination genes in the nervous system, beyond their well-documented roles in cell dismantling and removal. We describe relevant background on the C. elegans nervous system together with the apoptotic cell death and engulfment pathways, highlighting pioneering work in C. elegans. We discuss in detail the unexpected, atypical roles of cell elimination genes in various aspects of neuronal development, response and function. This includes the regulation of cell division, pruning, axon regeneration, and behavioral outputs. We share our outlook on expanding our thinking as to what cell elimination genes can do and noting their versatility. We speculate on the existence of novel genes downstream and upstream of the canonical cell death pathways relevant to neuronal biology. We also propose future directions emphasizing the exploration of the roles of cell death genes in pruning and guidance during embryonic development.

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CED-4 CARD domain residues can modulate non-apoptotic neuronal regeneration functions independently from apoptosis

Cited by 7 publications

References 35 publications

Regulation of defective mitochondrial DNA accumulation and transmission in C. elegans by the programmed cell death and aging pathways

Regulation of defective mitochondrial DNA accumulation and transmission in C. elegans by the programmed cell death and aging pathways

Age-associated changes to neuronal dynamics involve a disruption of excitatory/inhibitory balance in C. elegans

Repurposing the Killing Machine: Non-canonical Roles of the Cell Death Apparatus in Caenorhabditis elegans Neurons

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