Abstract
Motor neuron death in amyotrophic lateral sclerosis (ALS) is considered a “non-cell autonomous” process, with astrocytes playing a critical role in disease progression. Glial cells are activated early in transgenic mice expressing mutant SOD1, suggesting that neuroinflammation has a relevant role in the cascade of events that trigger the death of motor neurons. An inflammatory cascade including COX2 expression, secretion of cytokines and release of NO from astrocytes may descend from activation of a NF-κB-mediated pathway observed in astrocytes from ALS patients and in experimental models. We have attempted rescue of transgenic mutant SOD1 mice through the inhibition of the NF-κB pathway selectively in astrocytes. Here we show that despite efficient inhibition of this major pathway, double transgenic mice expressing the mutant SOD1G93A ubiquitously and the dominant negative form of IκBα (IκBαAA) in astrocytes under control of the GFAP promoter show no benefit in terms of onset and progression of disease. Our data indicate that motor neuron death in ALS cannot be prevented by inhibition of a single inflammatory pathway because alternative pathways are activated in the presence of a persistent toxic stimulus.
Highlights
Amyotrophic Lateral Sclerosis (ALS), the most common adultonset motor neuron disease, is usually fatal within five years of onset and is characterized by the degeneration of upper and lower motor neurons
Several cytokines have been proposed to play a role in ALS as reinforcing signals from glia cells, including interleukin-6 (IL6), tumour necrosis factor a (TNFa), monocyte chemoattractant protein-1, monocyte colonystimulating factor (MCSF) and transforming growth factor b1 (TGFb1) that were found increased in cerebrospinal fluid, plasma and epidermis from ALS patients, with sometimes conflicting results [14]
As demonstrated by two independent groups, astrocytes may be the primary cell types where mutant SOD1 exert its toxic effects on motor neurons by releasing some not yet identified molecule(s) [9,10]
Summary
Amyotrophic Lateral Sclerosis (ALS), the most common adultonset motor neuron disease, is usually fatal within five years of onset and is characterized by the degeneration of upper and lower motor neurons. 20% of familial cases are caused by mutations in the gene coding for Cu/Zn superoxide dismutase (SOD1), and following linkage studies published in 1993, many different transgenic animal and cellular models of human SOD1 mutations have been developed, increasing our knowledge about the pathogenesis of both sporadic and familial forms of ALS [2]. Motor neuron death in ALS is considered as a ‘‘non-cell autonomous’’ process, with astrocytes playing a critical role in disease progression [11]. The production of nitric oxide and the activation of cyclooxygenase type 2 (COX2) aggravate the toxic effects of mutant SOD1 in several experimental models for ALS. NF-kB activation has been observed in astrocytes from ALS patients and in human cells expressing mutant SOD1 [17]. Treatment with COX2 inhibitors markedly protects motor neurones and significantly prolongs survival of ALS mice [18]
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