IAPs are essential for GDNF-mediated neuroprotective effects in injured motor neurons in vivo

Abstract

During embryonic development, and in certain neurodegenerative diseases, neurons die by apoptosis. A new family of anti-apoptotic proteins, termed inhibitors of apoptosis (IAP), suppresses apoptosis through the direct inhibition of caspases. The anti-apoptotic activity of IAPs is inhibited by second mitochondria-derived activator of caspase (Smac)/DIABLO and XAF1 (ref. 8). IAPs, as well as neurotrophic factors, can protect degenerating neurons both in vivo and in vitro. However, the downstream targets of neurotrophic factors have not yet been identified. Here, we demonstrate that XIAP and NAIP, but not HIAP2, are directly involved in the intracellular response to glial cell-derived neurotrophic factor (GDNF). In newborn rats, GDNF regulates endogenous levels of XIAP and NAIP in motor neurons after sciatic nerve axotomy. The inhibition of XIAP or NAIP activity prevents GDNF-mediated neuroprotective effects. These results suggest that XIAP and NAIP are essential for intracellular signalling of GDNF in motor neuron survival.

Driving GDNF expression: The green and the red traffic lights

“…Consistent with these results, many studies report reduced number of lesion-induced TUNEL-positive cells in the presence of GDNF (Ghribi et al, 2001;Hermann et al, 2001;Zhang et al, 2001b;Jin et al, 2003;Ding et al, 2004;Dong et al, 2007). GDNF also regulates the levels of X-linked inhibitor of apoptosis (XIAP) and neuronal apoptosis inhibitory protein (NAIP; Perrelet et al, 2002). Furthermore, GDNF has an anti-excitotoxic effect on cortical neurons through the selective attenuation of NMDA-induced excitotoxic neuronal death by reducing NMDAinduced Ca 2+ influx (Nicole et al, 2001).…”

The inhibitors of apoptosis: there is more to life than Bcl2

“…Perhaps most significantly, functional rescue of memory and learning ability was demonstrated (Xu et al, 1997. Adenoviral vectors encoding NAIP, c-IAP1, and c-IAP2 have been shown to suppress apoptosis in the sciatic nerve axotomy model (Perrelet et al, 2000(Perrelet et al, , 2002, and adeno-XIAP in an optic nerve axotomy model (Kugler et al, 2000). Additionally, NAIP overexpression has been shown to be protective both histologically and functionally in the 6-hydroxydopamine model of Parkinson's disease (Crocker et al, 2001).…”

IAPS : More than just inhibitors of apoptosis proteins

“…In this way, BIRC1/NAIP, BIRC3/cIAP2 and BIRC4/XIAP have been involved in the survival of neurons, 17 cardiomyocytes 18 or macrophages 19 in stress conditions, and BIRC4/XIAP and BIRC6/Apollon seems important for mammary gland 20 and placenta 21,22 normal development respectively. New insights into the function of IAPs come from deletion experiments performed in Drosophila melanogaster that show that beside survival function, IAPs are important regulators of differentiation, 23,24 innate immune response [25][26][27][28] and cell motility.…”