**3. Indirect evidence for the role of QUIN in ALS**

In addition to the direct evidence demonstrating the link between the kynurenine pathway and ALS, numerous other studies have provided indirect evidence supporting the role of QUIN, in particular, in ALS.

### **3.1 QUIN and SOD1 expression**

Mutations in SOD1 constitute about 20% of familial ALS cases. In rat brain, intracerebral injection of QUIN resulted in significant neuronal loss and a markedly increased level of SOD1 expression in a time-dependent manner (Noack *et al.* 1998). This increase in SOD1 expression was thought to be a neuroprotective response to limit the oxidative damage caused by QUIN. Presumably, QUIN could have a similar effect on mutant SOD1, which would amplify the deleterious effects associated with mutant SOD1 pathology in ALS.

To date, the kynurenine pathway has been implicated in a wide range of diseases and disorders, including infectious diseases (e.g. HIV), neurological disorders (e.g. Alzheimer's disease (AD), Huntington's disease (HD) and ALS), affective disorders (e.g. schizophrenia, depression and anxiety), autoimmune diseases (e.g. multiple sclerosis and rheumatoid arthritis), peripheral conditions (e.g. cardiovascular disease) and malignancy, and a key indicator is often the up-

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

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

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

In addition to the direct evidence demonstrating the link between the kynurenine pathway and ALS, numerous other studies have provided indirect evidence supporting the role of

Mutations in SOD1 constitute about 20% of familial ALS cases. In rat brain, intracerebral injection of QUIN resulted in significant neuronal loss and a markedly increased level of SOD1 expression in a time-dependent manner (Noack *et al.* 1998). This increase in SOD1 expression was thought to be a neuroprotective response to limit the oxidative damage caused by QUIN. Presumably, QUIN could have a similar effect on mutant SOD1, which would amplify the deleterious effects associated with mutant SOD1 pathology in ALS.

regulation in IDO-1 resulting in an accelerated and sustained degradation in TRP.

adverse events exerted by QUIN leading to motor neuron injury and death.

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

involvement of the kynurenine pathway in ALS.

cytoplasmic inclusions (Taylor *et al.* 2007).

QUIN, in particular, in ALS.

**3.1 QUIN and SOD1 expression** 

**3. Indirect evidence for the role of QUIN in ALS** 

Fig. 3. Hypothetical model of the involvement of QUIN in the pathogenesis of ALS. QUIN, released from activated microglia, can induce various effects in astrocytes and motor neurons, including excitotoxicity, oxidative stress, apoptosis, mitochondrial dysfunction and the inflammatory cascade, all putatively thought to contribute to ALS disease pathogenesis and progression. Adapted from (Guillemin *et al.* 2005).
