**2. The kynurenine pathway and QUIN in ALS**

The interest in the kynurenine pathway in the pathogenesis of ALS is relatively new. However, a number of studies have provided relevant results demonstrating the involvement of the kynurenine pathway in ALS.

For the kynurenine pathway to be involved in the pathogenesis and progression of ALS, a key prerequisite has to be met – the activation of the immune response, particularly the presence of: (1) IFN-γ, which is the most potent stimulator of IDO-1 (Takikawa *et al.* 1999); and (2) activated microglia and/or infiltrating macrophages, which are the main producers of QUIN in the CNS (Brew *et al.* 1995; Heyes *et al.* 1996). Figure 3 summarizes the main adverse events exerted by QUIN leading to motor neuron injury and death.

A few studies have provided direct evidence between TRP metabolism and ALS. Patients with severe clinical status had significantly higher cerebrospinal fluid (CSF) KYNA levels compared to controls; however, serum KYNA levels were significantly lower in patients with severe clinical status compared to either controls or patients with mild clinical status (Ilzecka *et al.* 2003). This increase in CSF KYNA in patients was conjectured to be associated with the neuroprotective effect of KYNA, produced mainly by activated astrocytes (Guillemin *et al.* 2001). ALS samples have also been found to have significantly higher levels of CSF and serum KYN and QUIN and decreased levels of serum PIC (Chen *et al.* 2010).

Another study looked at Trp-32 in superoxide dismutase 1 (SOD1) protein. The aggregation of SOD1 is one of the hallmarks of familial ALS. Trp-32 is the only aromatic residue in SOD1 protein and is found on the SOD1 protein surface (Zhang *et al.* 2003). The oxidation of Trp-32 to KYN is responsible for bicarbonate mediated peroxidase activity induced SOD1 aggregation (Zhang *et al.* 2003). By substituting Trp-32 with phenylalanine, which oxidizes more slowly, mutant SOD-1 motor neurons survived longer and were less likely to form cytoplasmic inclusions (Taylor *et al.* 2007).
