sq-23377 and Down-Syndrome

Down syndrome (DS), the most common genetic disorder, is caused by trisomy 21. DS is accompanied by heart defects, hearing and vision problems, obesity, leukemia, and other conditions, including Alzheimer's disease (AD). In comparison, most cancers are rare in people with DS. Overexpression of dual specificity tyrosine-phosphorylation-regulated kinase 1A and a regulator of calcineurin 1 located on chromosome 21 leads to excessive suppression of the calcineurin-nuclear factor of activated T cells (NFAT) signaling pathway, resulting in reduced expression of a critical angiogenic factor. However, it is unclear whether the calcineurin-NFAT signaling pathway is involved in AD pathology in DS patients. Here, we investigated the association between the calcineurin-NFAT signaling pathway and AD using neuronal cells. Short-term pharmacological stimulation decreased gene expression of tau and neprilysin, and long-term inhibition of the signaling pathway decreased that of amyloid precursor protein. Moreover, a calcineurin inhibitor, cyclosporine A, also decreased neprilysin activity, leading to increases in amyloid-β peptide levels. Taken together, our results suggest that a dysregulation in calcineurin-NFAT signaling may contribute to the early onset of AD in people with DS.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Calcineurin; Calcineurin Inhibitors; Calcium Ionophores; Cell Line, Tumor; Cyclosporine; DNA-Binding Proteins; Down Syndrome; Humans; Intracellular Signaling Peptides and Proteins; Ionomycin; Luciferases; Muscle Proteins; Neprilysin; NFATC Transcription Factors; RNA, Messenger; Signal Transduction; tau Proteins; Tetradecanoylphorbol Acetate

Down syndrome is the most frequent genetic disorder in humans. Rare cases involving partial trisomy of chromosome 21 allowed a small chromosomal region common to all carriers, called Down Syndrome Critical Region (DSCR), to be determined. The DSCR1 gene was identified in this region and is expressed preferentially in the brain, heart and skeletal muscle. Recent studies have shown that DSCR1 belongs to a family of proteins that binds and inhibits calcineurin, a serine-threonine phosphatase. The work reported on herein consisted of a study of the subcellular location of DSCR1 and DSCR1-mutated forms by fusion with a green fluorescent protein, using various cell lines, including human.. The protein's location was preferentially nuclear, independently of the isoform, cell line and insertion in the GFP's N- or C-terminal. A segment in the C-terminal, which is important in the location of the protein, was identified by deletion. On the other hand, site-directed mutational analyses have indicated the involvement of some serine and threonine residues in this event.. In this paper, we discuss the identification of amino acids which can be important for subcellular location of DSCR1. The involvement of residues that are prone to phosphorylation suggests that the location and function of DSCR1 may be regulated by kinases and/or phosphatases.

Topics: Amino Acid Motifs; Animals; Calcineurin; Calcineurin Inhibitors; Cell Line; Chlorocebus aethiops; CHO Cells; COS Cells; Cricetinae; Cyclosporine; DNA-Binding Proteins; Down Syndrome; Humans; Intracellular Signaling Peptides and Proteins; Ionomycin; Kidney; Muscle Proteins; Mutagenesis, Site-Directed; Nuclear Proteins; Point Mutation; Proline; Protein Isoforms; Protein Sorting Signals; Serine; src Homology Domains; Tetradecanoylphorbol Acetate; Threonine