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  • br ASK in Huntington s disease

    2023-01-29


    ASK1 in Huntington's disease and other polyglutamine diseases The polyglutamine (polyQ) diseases are a group of inherited neurodegenerative disorders caused by the expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the coding regions of specific genes, leading to the production of pathogenic proteins containing critically expanded tracts of glutamines. To date, a total of nine polyQ disorders have been described: spinocerebellar ataxias (SCA) types 1, 2, 6, 7, and 17; Machado-Joseph disease (MJD/SCA3); Huntington's disease (HD); dentatorubral-pallidoluysian atrophy (DRPLA); and spinal and bulbar muscular atrophy, X-linked 1 (SMAX1/SBMA). These nine diseases are irreversibly progressive over 10–30 years, severely impairing, and ultimately fatal. In these diseases, pathogenic proteins with expanded polyQ repeats form insoluble aggregates, which disturb the ubiquitin-proteasome system and cause ER stress, resulting in neuronal cell death (Nishitoh et al., 2002). HD, a representative of polyQ diseases, is an autosomal, dominantly inherited disorder. HD is caused by the expansion of polyQ repeats in the N-terminus of the huntingtin Cyt387 (htt) protein and is characterized pathologically by the degeneration of striatal and cortical neurons and the appearance of neuronal inclusions. ASK1 has been shown to be involved in the pathogenesis of polyQ diseases including HD (Nishitoh et al., 2002). In vitro experiments using primary cultured neurons revealed that neuronal cell death caused by JNK activation, which is induced by expanded polyQ repeats and ER stress, was inhibited by ASK1-deficiency (Nishitoh et al., 2002). In addition, increased ASK1 expression and ER stress in the striatum and Cyt387 was found in HD model mice expressing exon 1 of the human HD gene (Cho et al., 2009), and high levels of phosphorylated c-Jun, a major substrate of JNK, have been shown in a rat model of HD (Perrin et al., 2009). These results indicate that ER stress activates the ASK1-JNK pathway in vivo. Consistently, ASK1 inhibition with an anti-ASK1 antibody prevents atrophy of striatal neurons and improves motor function in HD model mice (Cho et al., 2009). Moreover, elevated ASK1 activity was found in an oxidative-stress- and age-dependent manner in mice with HD-like brain lesions that are induced by the injection of the mitochondrial complex II inhibitor 3-nitropropionic acid (3-NP) (Minn et al., 2008). Infusion of ASK1 siRNA prevents 3-NP-induced neuronal cell death (Minn et al., 2008). In addition, it was demonstrated using allelic analysis in HD patients that sequence variations of the MAP3K5 and MAP2K6 genes, encoding ASK1 and MKK6 respectively, appear to modify the age of HD onset (Arning et al., 2008). It is also reported that another polyQ protein, ataxin-1 (ATXN1), has an important role in the pathogenesis of SCA1 (Ryu et al., 2010). ATXN1 has been shown to activate the ASK1-JNK pathway, promoting the sumoylation and aggregation of ATXN1, which might lead to neuronal cell death in SCA1 (Ryu et al., 2010). Taken together, these findings suggest an important role of ASK1 in polyQ diseases.
    ASK1 in other neurodegenerative diseases ASK1 is also reported as playing important roles in other neuronal diseases. Among them, mesial temporal lobe epilepsy (MTLE) is associated with hippocampal sclerosis and is frequently resistant to medications (Cendes et al., 2014). MTLE accounts for almost 80% of all temporal lobe seizures, the most common form of partial or localization-related epilepsy. In the hippocampi of patients with MTLE, the expression of ASK1 and the activation of both JNK and the ER-stress-associated kinase inositol-requiring enzyme 1 (IRE1) are found to be upregulated (Liu et al., 2011). Progressive cervical cord compression, the most common cause of spinal cord dysfunction in people over 55 years old, may occur because of the narrowing of the spinal canal by osteophytes, the loss of axons and oligodendrocytes in the white matter, the loss of neurons in the gray matter (Yu et al., 2009), and the ossification of the posterior longitudinal ligament (OPLL) leading to myelin destruction. Using tiptoe-walking Yoshimura (TWY) mice, a mouse model of progressive cervical cord compression, it has recently been shown that the ASK1-JNK/p38 pathways are activated in both the neurons and oligodendrocytes of compressed spinal cords (Takenouchi et al., 2008). Studies of the genetic or pharmacological manipulation of ASK1 will shed new insights on its roles in these neurodegenerative diseases.