, 2007). Interestingly, conditioned media from ALS1 SOD1 mouse microglia, cortical neurons, myocytes, or fibroblasts was not toxic to motor neurons—only conditioned media from ALS1 SOD1 mutant astrocytes possessed this property. Although the specific molecule or protein responsible for mutant SOD1 astrocyte toxicity eluded identification in this study, SOD1 and glutamate were ruled out as the offending substance (Nagai et al., 2007). Defining the nature of this astrocyte-derived click here soluble toxin could yield crucial insights into ALS disease pathogenesis and may have therapeutic implications. The clinical

relevance of astrocyte-mediated neurotoxicity for FALS and SALS was recently demonstrated by a provocative study in which neural progenitor cells derived Ibrutinib from the spinal cords of FALS and SALS patients and differentiated into astrocytes were sufficient to kill cocultured motor neurons (Haidet-Phillips et al., 2011).

Interestingly, this study indicated that SOD1 appears to contribute to the neurotoxicity imparted by SALS and FALS astrocytes, as knockdown of SOD1in these astrocytes suppressed motor neuron toxicity. Innate immune responses include the initial cellular and molecular reaction to the detection of pathogens or tissue injury. Key components of the CNS innate immune response include the complement cascade and cells capable of performing phagocytosis, generating reactive oxygen species and signaling via cytokines, chemokines, and additional immunomodulatory small molecules to other cells involved

in the response to injury or pathogens. Evidence for the activation of the CNS innate immune response in neurodegenerative diseases have been extensively documented and recently reviewed (Prinz Cytidine deaminase et al., 2011). However, the mechanisms by which neuronal injury is signaled to the immune system, and how this immune response may subsequently influence the progression of the disease, have only recently been elucidated. The principal mechanism through which an innate immune response is initiated, involves signaling through the TLR family of receptors (Crack and Bray, 2007 and Kielian, 2006). TLR receptors were initially discovered for their role in binding a variety of pathogen associated molecular pattern (PAMP) ligands common to pathogenic organisms (Akira et al., 2001). More recently however, it has become clear that injured cells, including neurons (Sloane et al., 2010), release a class of molecules known as “danger associated molecular pattern” (DAMP) ligands that also bind to TLR receptors and initiate an innate immune response. The DAMP/TLR signaling pathway, in addition to release of the chemokine CX3CL1 (previously known as fractalkine) by injured neurons (Streit et al., 2005), explain how innate CNS immune response can produce a strong inflammatory reaction, in the absence of pathogens, that may impact disease onset and progression.