👤 Katsuyoshi Takata

In a series of studies on blood-brain barrier transportable peptides, a soybean dipeptide, Tyr-Pro, penetrated the mouse brain parenchyma after oral intake and improved short and long memory impairment in acute Alzheimer's model mice. Here, we aimed to clarify the anti-dementia effects of this peptide administered to SAMP8 mice prior to dementia onset. At the end of the 25-week protocol in 16-week-old SAMP8 mice, Tyr-Pro (10 mg/kg/day) significantly improved the reduced spatial learning ability compared with that in the control and amino acid (Tyr + Pro) groups as indicated by the results of Morris water maze tests conducted for five consecutive days. The hippocampus and cortex regions of SAMP8 harvested after the test showed lower amyloid ß (Aß) accumulation in the Tyr-Pro group than those in the control and amino acid groups. Consistent with the lower level of Aß, decreased expression of ß-secretase (BACE1) and markedly increased expression (4-times higher) of insulin degrading enzyme (IDE) were obtained compared to those in the control group. Collectively, we demonstrated that long-term daily intake of the dipeptide Tyr-Pro in SAMP8 mice may be sufficient for maintaining cognitive ability by preventing excess Aß accumulation through downregulated BACE1 and particularly upregulated IDE. Show less

Large-scale genome-wide association studies (GWASs) on bipolar disorder (BD) have implicated the involvement of the fatty acid desaturase (FADS) locus. These enzymes (FADS1 and FADS2) are involved in the metabolism of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are thought to potentially benefit patients with mood disorders. To model reductions in the activity of FADS1/2 affected by the susceptibility alleles, we generated mutant mice heterozygously lacking both Fads1/2 genes. We measured wheel-running activity over six months and observed bipolar swings in activity, including hyperactivity and hypoactivity. The hyperactivity episodes, in which activity was far above the norm, usually lasted half a day; mice manifested significantly shorter immobility times on the behavioral despair test performed during these episodes. The hypoactivity episodes, which lasted for several weeks, were accompanied by abnormal circadian rhythms and a marked decrease in wheel running, a spontaneous behavior associated with motivation and reward systems. We comprehensively examined lipid composition in the brain and found that levels of certain lipids were significantly altered between wild-type and the heterozygous mutant mice, but no changes were consistent with both sexes and either DHA or EPA was not altered. However, supplementation with DHA or a mixture of DHA and EPA prevented these episodic behavioral changes. Here we propose that heterozygous Fads1/2 knockout mice are a model of BD with robust constitutive, face, and predictive validity, as administration of the mood stabilizer lithium was also effective. This GWAS-based model helps to clarify how lipids and their metabolisms are involved in the pathogenesis and treatment of BD. Show less

Rett syndrome (RTT) is a characteristic neurological disease presenting with regressive loss of neurodevelopmental milestones. Typical RTT is generally caused by abnormality of methyl-CpG binding protein 2 ( We performed WES on 77 Pathogenic or likely pathogenic single-nucleotide variants in 28 known genes were found in 39 of 77 (50.6%) patients. WES-based CNV analysis revealed pathogenic deletions involving six known genes (including Our study provides a new landscape including additional genetic variants contributing to RTT-like phenotypes, highlighting the importance of comprehensive genetic analysis. Show less

Multiple osteochondromas is a dysplasia characterized by growth of two or more osteochondromas. It is genetically heterogeneous, caused by pathogenic variants in EXT1 or EXT2 genes in 70%-90% of patients. The EXT1 is more often mutated than EXT2 gene, with a variable prevalence between populations. There are no data about EXT1 and EXT2 pathogenic variants in patients with multiple osteochondromas in Brazilian population. The aim of this survey is to characterize these to determine the genotype profile of this population. DNA sequencing (Sanger Method) and MLPA analysis were performed to identify point mutations and deletions/duplications in the sample of 153 patients in 114 families. Germline variants were identified in 83% of families in which EXT2 variants were detected in 46% and EXT1 in 37% of cases. No variants were detected in 17% of them. We identified 50 different variants, 33 (13 frameshift, 11 nonsense, 5 missense, 2 splice site mutation, and 2 large deletions) in EXT1 and 17 (6 frameshift, 6 splice site mutation, 3 nonsense, 1 missense, and 1 large deletion) in EXT2. Of all 50 variants, 31 (62%) were novel, including 20 out of 33 (60,6%) EXT1 and 11 out of 17 (64.7%) EXT2 alleles. The vast majority of variants (88%) were "loss-of-function" and two novel hotspots in EXT2 gene were observed in our study. The prevalence of variants detected in the EXT2 gene differs from other researches from Latin America, European, and Asian population. This uncommon prevalence could be related with the newly characterized variant hotspot sites detected in EXT2 gene (p.Ala409Profs*26 and p.Ser290*). A high number of novel variants were also identified indicating that Brazilian population has a unique genetic profile. Characterizing this population and establishing its genotype is essential to understand the molecular pathogenesis of this disease in Brazil. Show less

We propose Langerhans cell histiocytosis (LCH) is an inflammatory process that is prolonged by mutations. We hypothesize that Merkel cell polyomavirus (MCPyV) infection triggers an interleukin-1 (IL-1) activation loop that underlies the pathogenesis of LCH. Langerhans cells (LCs) are antigen presenting cells in the skin. When LCs encounter exogenous antigens, they migrate from the epidermis into draining lymphoid tissues to initiate T-cell activity. It has been proposed that LC migration-related factors, including E-cadherin, matrix metalloproteinase, and Notch ligand induce LCH activity. We found that the tyrosine phosphatase SHP-1, which binds IL-1 receptor-associated kinase 1, is expressed at a significantly higher level in LCH affecting multiple organ systems (MS-LCH) than in LCH affecting a single organ system (SS-LCH). IL-1 stimulates T helper 17 cells and their signature cytokine IL-17 had been a matter of controversy. We detected higher levels of IL-17A receptor expression in MS-LCH than in SS-LCH and proposed an IL-17 endocrine model that could settle the controversy. IL-1 is the first cytokine secreted in response to sensitizers and promotes LC migration from sentinel tissues. Myeloid differentiation primary response 88 (MyD88), downstream of the IL-1 receptor, has functions in both RAS signaling and inflammation, leading to human cell transformation. In 2010, an activating mutation in the B-rapidly accelerated fibrosarcoma gene (BRAF) V600E was found in LCH. This BRAF mutation induces phosphorylation of the extracellular signal-regulated kinase (ERK) that may play an important role with MyD88 in LCH pathogenesis. However, phosphorylated ERK (pERK) is rapidly dephosphorylated by dual specificity phosphatase 6 (DUSP6), and limited proliferation is predicted in BRAF mutant cells. MyD88 binds pERK via its D-domain, thereby preventing pERK-DUSP6 interaction and maintaining ERK in an active, phosphorylated state. We detected MCPyV-DNA in the peripheral blood cells of two out of three patients with LCH in high-risk organs but not in those of patients with LCH in non-high-risk organs (0/12; P = .029). MCPyV infection can trigger precursor LCH cells with BRAF mutation to produce IL-1; the IL-1 loop is amplified in all LCH subclasses. Our model indicates both BRAF mutation and IL-1 loop regulation as potential therapeutic targets. Show less

The Hairy-related bHLH proteins function as transcriptional repressors in most cases and play important roles in diverse aspects of metazoan development. Recently, it was shown that the Drosophila bHLH repressor proteins, Hairy and Deadpan, bind to and function with the NAD(+)-dependent histone deacetylase, Sir2. Here we demonstrate that the human Sir2 homologue, SIRT1, also physically associates with the human bHLH repressor proteins, hHES1 and hHEY2, both in vitro and in vivo. Moreover, using the reporter assay, we show that both SIRT1-dependent and -independent deacetylase pathways are involved in the transcriptional repressions mediated by these bHLH repressors. These results indicate that the molecular association between bHLH proteins and Sir2-related proteins is conserved among metazoans, from Drosophila to human, and suggest that the Sir2-bHLH interaction also plays important roles in human cells. Show less