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  • BAY 41-8543 receptor PD research involves the use of many

    2023-01-04

    PD research involves the use of many animal models, which can be categorized into two main types: toxic models—among which the two most widely used are the classical 6-hydroxydopamine (6-OHDA) model in rats and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model in mice and monkeys—and genetic models such as the α-synuclein model in transgenic mice and the PTEN-induced putative kinase 1 (PINK1) KO model in mice (Blesa and Przedborski, 2014, Koyano et al., 2014). To exert its toxicity in vivo, MPTP is first converted to MPP+, and ASK1 in dopamine neurons relays the signals originating from MPP+ to produce the BAY 41-8543 receptor responsible for glial activation, such as cyclooxygenase-2. ASK1 activation in the substantia nigra has been reported in wild-type mice with systemic exposure to MPTP (Lee et al., 2012), and dopaminergic neuronal loss in ASK1 KO mice was dampened along with reduced inflammatory indicators and less pronounced motor impairment. This suggests that ASK1 signaling plays an important role as a link between oxidative stress and neuroinflammation in MPTP-induced toxicity in mice (Lee et al., 2012). Moreover, a similar trend of diminished 6-OHDA toxicity was found in the mouse nigra with shRNA mediated ASK1 knockdown (Hu et al., 2011). It will be interesting to investigate whether the pharmacological inhibition of ASK1 improves PD symptoms.
    ASK1 in amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that primarily affects the motor neurons in the motor cortex, brainstem, and spinal cord, resulting in progressive muscle weakness (Rowland and Shneider, 2001). In the Western world, ALS has an incidence rate of 1–2 individuals per 100,000 per year and a prevalence of 4–8 individuals per 100,000 (Logroscino et al., 2010). In approximately 10% of ALS patients, the disease runs in the family (familial ALS, FALS), and approximately 90% are classified as having sporadic ALS. One gene responsible for 2% of ALS cases is Cu/Zn-superoxide dismutase 1 (SOD1) whose mutation specifically causes motor neuron death (Wijesekera and Leigh, 2009). In addition, studies on other causative genes, such as TDP-43 and FUS that can induce the misfolding and/or aggregate formation of SOD1WT, have provided new insights into the pathogenesis of ALS, suggesting that ALS cannot be explained solely by the SOD1 mutation (Hayashi et al., 2016). Moreover, several factors including excitotoxicity, oxidative stress and ER stress have been proposed to be involved in the neurotoxicity associated with mutant SOD1 species (Hayashi et al., 2016). In FALS model mice expressing the ALS-linked SOD1 mutant (SOD1(mut)), activation of ASK1 and p38, which is concomitant with motor neuron death, was revealed by immunohistochemical analysis (Holasek et al., 2005, Veglianese et al., 2006, Wengenack et al., 2004). In elucidating the mechanism how SOD1(mut) activates ASK1, Nishitoh et al. reported an interaction of SOD1(mut) with the putative ER translocon degradation in endoplasmic reticulum protein 1 (Derlin-1) (Nishitoh et al., 2008), which they hypothesized might induce ER stress and ASK1 activation, resulting in cell death (Nishitoh et al., 2008). They confirmed the hypothesis by showing that a polypeptide of the cytosolic region of Derlin-1, which disrupts the SOD1(mut)-Derlin-1 interaction, inhibited SOD1(mut)-induced cell death (Nishitoh et al., 2008). Moreover, motor neuron loss was attenuated in ASK1-deficient FALS model mice, leading to longer lifespans (Nishitoh et al., 2008). In addition, the oral administration of K811 or K812, selective inhibitors of ASK1, significantly extend the lifespans of SOD1(G93A) transgenic mice (Fujisawa et al., 2016). Activation of the p38 cascade was found in the spinal motor neurons of mouse models of FALS, and SOD1(mut)-induced motor neuron degeneration was reduced by the p38 inhibitor semapimod (Dewil et al., 2007, Veglianese et al., 2006). Hence, the ASK1-p38 pathway could be a promising target for the treatment of ALS.