Axon Degeneration Gated by Retrograde Activation of Somatic Pro-apoptotic Signaling

Abstract

During development, sensory axons compete for limiting neurotrophic support, and local neurotrophin insufficiency triggers caspase-dependent axon degeneration. The signaling driving axon degeneration upon local deprivation is proposed to reside within axons. Our results instead support a model in which, despite the apoptotic machinery being present in axons, the cell body is an active participant in gating axonal caspase activation and axon degeneration. Loss of trophic support in axons initiates retrograde activation of a somatic pro-apoptotic pathway, which in turn is required for distal axon degeneration via an anterograde pro-degenerative factor. At a molecular level, the cell body is a convergence point of two signaling pathways whose integrated action drives upregulation of pro-apoptotic Puma, which, unexpectedly, is confined to the cell body. Puma then overcomes inhibition by pro-survival Bcl-xL and Bcl-w and initiates the anterograde pro-degenerative program, highlighting the role of the cell body as an arbiter of large-scale axon removal.

Paclitaxel Reduces Axonal Bclw to Initiate IP3R1-Dependent Axon Degeneration

“…Although anti-apoptotic Bcl2 family members are involved in developmental axon degeneration, it is uncertain whether Bcl2 family members are also critical for axon degeneration caused by injury or disease (Cosker et al, 2013; Courchesne et al, 2011; Nikolaev et al, 2009; Pazyra-Murphy et al, 2009; Schoenmann et al, 2010; Simon et al, 2016; Simon et al, 2012; Vohra et al, 2010). To determine if Bcl2 family members are implicated in paclitaxel-induced axon degeneration, we examined expression of the anti-apoptotic components Bclw (Bcl2l2), Bcl2, or Bclx L (Bcl2l1) after paclitaxel treatment.…”

“…Pathological axon degeneration involves aberrant calcium signaling, changes in mitochondrial function, and activation of calpain proteases. Bcl2 family members, which are implicated in developmental axon pruning (Cosker et al, 2016; Cosker et al, 2013; Courchesne et al, 2011; Pazyra-Murphy et al, 2009; Schoenmann et al, 2010; Simon et al, 2016; Simon et al, 2012; Vohra et al, 2010), are capable of regulating mitochondrial morphology and calcium homeostasis (Chipuk et al, 2010). However, it is not yet known if pathological axon degeneration involves Bcl2 components.…”

FOXO in Neural Cells and Diseases of the Nervous System

“…Shortly thereafter this pathway was also described in motor neurons and it was suggested that FasL and JNK signaling might be partially responsible for FOXO3-induced death (Barthelemy, Henderson & Pettmann, 2004). Most recently AKT/FOXO3 signaling has been shown to be of central importance in neuronal cell death triggered from the axon that signals back to the cell body to commence apoptosis following NGF withdrawal (Simon et al, 2016). FOXO1 has also been shown to regulate apoptosis downstream of AKT in neurons.…”

FOXO protects against age‐progressive axonal degeneration

“…The activation of the pro‐survival phosphoinositide‐3 kinase (PI3K)–AKT pathway protected against neuronal cell death in cases of nerve growth factor withdrawal, while the activation of FOXO in this context promoted cell death (Simon et al., 2016). Neuroprotective NMDA receptor signaling by PI3K–AKT activation inhibited FOXO‐dependent gene expression to suppress oxidative stress in neurons (Papadia et al., 2008).…”