Fas small interfering RNA reduces motoneuron death in amyotrophic lateral sclerosis mice

Abstract

Fas silencing interferes with motoneuron-specific downstream death pathways and results in increased motoneuron survival and amelioration of the SOD1-G93A phenotype, suggesting new possible strategies for molecular therapy of ALS.

IFNγ triggers a LIGHT-dependent selective death of motoneurons contributing to the non-cell-autonomous effects of mutant SOD1

“…14,15 Interestingly, a functional involvement of the Fas death pathway in motoneuron degeneration in mutant SOD1 mice has been shown. [15][16][17] Regarding the pathogenic processes, the mutant astrocyte-mediated toxicity to motoneurons would occur independently of the Fas death pathway, 8 suggesting that other sources, such as microglia or serum, activate Fas. 14,18 Our understanding of the selective degenerative process integrating external death triggers remains, however, incomplete.…”

The BCL-2 family protein Bid is critical for pro-inflammatory signaling in astrocytes

“…IFNγ may also co-6 operate with TNF-α to induce oxidative stress (Hanisch, 2002;Mir et al, 2009). mouse (Raoul et al, 2002;Locatelli et al, 2007). Our data suggest that Bid, in addition to 10 a role in death receptor-induced apoptosis of motoneurons, may play a role in non-cell 11 autonomous motoneuron death by controlling NF-κB activity in astroglia.…”

“…Interleukin-1β (IL-1β) and Interferon-γ (IFNγ) have been 13 implicated in ALS disease progression (Friedlander et al, 1997;Meissner et al, 2010;14 Wang et al, 2011). Motoneuron apoptosis in ALS was also shown to involve Fas ligand 15 up-regulation and activation of Fas death receptors (Locatelli et al, 2007;Raoul et al, 16 2002). Release of pro-inflammatory cytokines may lead to death receptor and caspase-8 17 activation, which is able to directly activate executioner caspases such as caspase-3 18 (Locatelli et al, 2007;Raoul et al, 2002).…”

“…Motoneuron apoptosis in ALS was also shown to involve Fas ligand 15 up-regulation and activation of Fas death receptors (Locatelli et al, 2007;Raoul et al, 16 2002). Release of pro-inflammatory cytokines may lead to death receptor and caspase-8 17 activation, which is able to directly activate executioner caspases such as caspase-3 18 (Locatelli et al, 2007;Raoul et al, 2002). However, in most cell types, this direct activation 19 pathway is not sufficient to activate apoptosis, and an amplification loop is required for cell 20 death execution that involves the BH3-only protein Bid, and hence engages the 21 mitochondrial apoptosis pathway (Lovell et al, 2008;Luo et al, 1998 (Guegan et al, 2002).…”

Role of Mitochondrial Dysfunction in Motor Neuron Degeneration in ALS

“…This drug was effective in delaying the motor neurons loss when given prior to the symptoms onset, but when given at late stages it exaggerated the neuroinflammatory response and accelerated the progression of the symptoms . In this transgenic ALS model, apoptosis processes can be triggered by non-neuronal cells through the extrinsic apoptotic pathway, via the release from activated glial cells of several death ligands (for example FasL) that bind to their respective death receptor (Fas) and trigger the cleavage of caspase-8 (Locatelli et al, 2007;Petri et al, 2006;Raoul et al, 2006) (Fig. 1).…”