Humanin receptor or humanin-like polypeptide receptor
Technical field
The present invention relates to humanin receptor or humanin-like polypeptide receptor (hereinafter collectively referred to as "HNR"), transformed cells forcibly expressing the receptor, screening methods for compounds binding to the receptor, pharmaceutical compositions containing the compounds, etc. This application is based on Japanese patent application No. 2005-124394 filed on April 22, 2005 and Japanese patent application No. 2005-255972 filed on September 5, 2005, and claims priority thereto, and the contents thereof are all cited in this specification and are deemed to be part of the disclosure.
Background technology
Neurogenicity is believed to be directly related to the expression of the main neurological signs or symptoms of Alzheimer's disease (AD). Its pathological mechanism is not yet understood, but it is the most important target for AD treatment. Various AD-related injuries, i.e., overexpression of familial AD (FAD) gene mutants or increase and addition of toxic amyloid β (Aβs) from amyloid β precursor (APP), etc. induce neuronal cell death in vitro through various pathways.
It has been found that missense mutations in three genes - APP, presenilin 1 (PS1), and presenilin 2 (PS2) - are causative in familial AD (FAD) (Shastry and Ginlin, 1999). It is not clear how these mutant genes cause neuronal loss in vivo in FAD brains, but several research groups have demonstrated that expression of FAD-related APP and PS gene mutants causes neuronal cell death in cultured cells (Yamatsuji et al., 1996a, b; Wolozin et al., 1996; Zhao et al., 1997; Nishimura et al., 1998; Luo et al., 1999; Hashimoto et al., 2000) or in primary cultured cortical neurons (PCNs) (Niikura et al., 2004). Furthermore, the increase of amyloid-β, which is considered to be closely related to AD pathology (Hardy and Selkoe, 2002), is a physiologically high concentration and has been shown to induce neuronal cell death in vitro (Loo et al., 1994; Hashimoto et al., 2001; Hashimoto et al., 2004). The present inventors used a cDNA library prepared from the occipital lobe of the brain dissected after death of AD patients, and identified a cDNA encoding a 24-amino acid peptide MAPRGFSCLLLLTSEIDLPVKRRA named Humanin (HN) by a functional screening method "destroyer screening method" that does not impose bias on compounds that prevent cell death (Patent Document 1). HN has shown antagonistic effects on neuronal cell death caused by all AD-related damage, such as various FAD genes or anti-APP antibodies, and amyloid-β peptide (Aβ) (Hashimoto et al., 2001a and b., Nishimoto et al., 2004). HN showed complete antagonism at 10 μM. In addition, in subsequent studies, HN was shown to antagonize certain neuronal or non-neural cell death, such as cell death of PC12 (Kariya et al., 2002) or lymphocytes (Kariya et al., 2003) in serum-free culture medium, or AD-induced human cerebrovascular smooth muscle cell toxicity (Jung et al., 2003), and neurotoxicity caused by peptides from prions (Sponne et al., 2004).
We reported that HN is secreted from cells and mediated by cell surface receptors to antagonize neuronal cell death caused by AD-related damage from outside the cell.
Recently, Ying et al. (2004) reported that in PC12 cell lines, HN antagonized neuronal cell death caused by Aβ(1-42) by binding to the PTX-sensitive G protein-bound receptor-human formyl peptide receptor-like-1 (FPRL-1) receptor. Ying et al. reported that HN showed an antagonistic effect on Aβ-induced neurotoxicity due to its competitive inhibition of Aβ binding to FPRL-1. However, when investigating whether FPRL-1 is involved in the neuroprotective effect of HN against AD-related damage, it was found that FPRL-1 was not involved in the neuroprotective effect of HN in F11 neural hybrid cell lines or primary cultured cortical neurons (PCNs), and pointed out that there are receptors other than FPRL-1 in this system, and HN exerts neuroprotective effects through these receptors.
Our study showed that STAT3 and a certain tyrosine kinase are involved in the neuroprotective effect of HN, indicating the presence of cytokine receptor-like receptors in this signaling pathway.
gp130 is a common cytokine receptor subunit in the interleukin 6 (IL-6) receptor family. Receptors containing gp130 are stimulated by Th1-type cytokines including IL-6, IL-11, LIF, CNTF, oncostatin (OSM), cardiotrophin-1, or IL-27. The binding of these cytokines to the receptor induces homodimerization of gp130 or heterodimerization of gp130 with related receptors, such as LIF receptor, OSM receptor, WSX-1 (IL27 receptor), and transmits the signal of the cytokine to the intracellular signaling pathway mediated by the JAK/STAT or RAS/MAPK signaling pathway (Raga et al., 1997; Boulay et al., 2003; Boulanger et al., 2004). Recent studies have shown that IL-27 (IL-27p28/EBV-induced gene 3), which belongs to the IL-6/IL-12 cytokine family, binds to WSX-1/gp130 (Pflanz et al., 2004) and is shown to control Th1 and Th2 immune responses (Yoshida et al., 2004). It is also known that CNTF-R is a gp130-related receptor that does not have an intracellular signaling domain.
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