Endoplasmic reticulum stress-induced apoptosis requires bax for commitment and Apaf-1 for execution in primary neurons

Abstract

Apoptosis triggered by endoplasmic reticulum (ER) stress is associated with various pathophysiological conditions including neurodegenerative diseases and ischemia. However, the mechanism by which ER stress induces neuronal apoptosis remains controversial. Here we identify the pathway of apoptosis carried out in sympathetic neurons triggered to die by ER stressinducing agent tunicamycin. We find that ER stress induces a neuronal apoptotic pathway which upregulates BH3-only genes DP5 and Puma. Importantly, we show that ER stress commits neurons to die before cytochrome c release and this commitment requires Bax activation and c-jun N-terminal kinase signaling. Furthermore, ER stress engages the mitochondrial pathway of death as neurons release cytochrome c and Apaf-1 deficiency is sufficient to block apoptosis. Our findings identify a critical function of Bax in committing neurons to ER stress-induced apoptosis and clarify the importance of the apoptosome as the non-redundant caspase activation pathway to execute neuronal apoptosis in response to ER stress.

Cytoplasmic Inclusions of Htt Exon1 Containing an Expanded Polyglutamine Tract Suppress Execution of Apoptosis in Sympathetic Neurons

“…and Deshmukh, 2007). These data indicate that the early toxicity that occurred after infection with Ad-Q25 was apoptotic.…”

Tissue inhibitor of metalloproteinases-3 (TIMP-3) expression is increased during serum deprivation-induced neuronal apoptosis in vitro and in the G93A mouse model of amyotrophic lateral sclerosis: A potential modulator of Fas-mediated apoptosis

“…Apaf-1, together with cytochrome C and caspase-9, forms the apoptosome, which is an essential component of mitochondrion-dependent apoptosis (Chen and Wang, 2002). Apaf-1 has been shown to mediate neuronal apoptosis in cultured cells exposed to beta amyloid or endoplasmic reticulum (ER) stress (Li et al, 2004;Smith and Deshmukh, 2007) and also in various animal models of nervous system diseases such as traumatic spinal cord injury, Parkinson's disease, and transient cerebral ischemia (Springer et al, 1999;Mochizuki et al, 2001;Cao et al, 2002). TIMP-3 can act as a pro-apoptotic protein in cancer cell lines, possibly through stabilization of death receptors and protection against proteolytic cleavage by metalloproteinases (Ahonen et al, 2003).…”

The endoplasmic reticulum in apoptosis and autophagy: role of the BCL-2 protein family

“…Cytochrome c release, loss of mitochondrial membrane potential and caspase-9 activation are seen in response to a variety of ER stressors (Hacki et al, 2000;Boya et al, 2002;Jimbo et al, 2003;Kitamura et al, 2003;Masud et al, 2007;Wlodkowic et al, 2007), and the loss of Apaf 1 (which is required, along with cytochrome c, for postmitochondrial caspase-9 activation) significantly decreases ER stressinduced apoptosis in a variety of experimental systems (Di Sano et al, 2006;Shiraishi et al, 2006;Smith and Deshmukh, 2007), as does the inhibition of mitochondrial permeability transition (involved in the release of mitochondrial cytochrome c (Kinnally and Antonsson, 2007)) (Zhang and Armstrong, 2007;Deniaud et al, 2008;Zhang et al, 2008). In addition, the activation and mitochondrial localization of BAX are seen in response to ER stress, and several studies have shown that mitochondrial BAX is required for ER stress-initiated apoptosis Shiraishi et al, 2006;Zhang and Armstrong, 2007;Deniaud et al, 2008;Zhang et al, 2008).…”