While studies on death receptors have long been restricted to immune cells, the last decade has provided a strong body of evidence for their implication in neuronal death and hence neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). ALS is a fatal paralytic disorder that primarily affects motoneurons in the brain and spinal cord. A neuroinflammatory process, associated with astrocyte and microglial activation as well as infiltration of immune cells, accompanies motoneuron degeneration and supports the contribution of non-cell-autonomous mechanisms in the disease. Hallmarks of Fas, TNFR, LT-βR, and p7 signaling have been observed in both animal models and ALS patients. This review summarizes to date knowledge of the role of death receptors in ALS and the link existing between the selective loss of motoneurons and neuroinflammation. It further suggests how this recent evidence could be included in an ultimate multiapproach to treat patients. 1. Introduction The name of “death receptors” is associated with the tumor necrosis factor receptor superfamily (TNFRSF) of transmembrane proteins whose first shown function was to induce apoptosis in subtypes of immune cells (for review see [1]). For example, Fas (CD95, Apo1) was identified in 1989 as a receptor being activated during the negative and positive selection of T cells [2, 3]. Since this pioneer work, death receptor activation has been evidenced in a variety of nonimmune cells and shown to induce, besides apoptosis, a number of nonapoptotic events including regulation of cell proliferation and differentiation, chemokine production, inflammatory responses, and tumor-promoting activities [4]. In the nervous system, most death receptors are expressed by neurons as well as by glial cells during development. Nevertheless, while activation of Fas or TNFR induces death of embryonic nervous cells in vitro [5–7], there is still little evidence about their implication in developmental cell death. On the contrary, a growing body of data has demonstrated the involvement of death receptors in neurodegenerative diseases. Depending on models and experimental conditions, studies have confirmed the proapoptotic effects resulting from the activation of death receptors in Alzheimer’s disease [8, 9] or in Parkinson’s disease [10] but have also pointed out their nonapoptotic functions in cell protection in Parkinson’s disease [11, 12]. Probably the strongest evidence for the involvement of death receptors in neurodegenerative diseases comes from studies on amyotrophic lateral sclerosis (ALS). ALS is a
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