Biology subjects

Sugawara, H.

Publications and source records attributed to Sugawara, H..

3 recordsLinked to original sources

bioRxiv2020

Promoter activity-based case-control association study on SLC6A4 highlighting hypermethylation and altered amygdala volume in male patients with schizophrenia

Associations between altered DNA methylation of the serotonin transporter (5-HTT)-encoding gene SLC6A4 and early life adversity, mood and anxiety disorders, and amygdala reactivity have been reported. However, few studies have examined epigenetic alterations of SLC6A4 in schizophrenia (SZ). We examined CpG sites of SLC6A4, whose DNA methylation levels have been reported to be altered in bipolar disorder, using three independent cohorts of patients with SZ and age-matched controls. We found significant hypermethylation of a CpG site in SLC6A4 in male patients with SZ in all three cohorts. We showed that chronic administration of risperidone did not affect the DNA methylation status at this CpG site using common marmosets, and that in vitro DNA methylation at this CpG site diminished the promoter activity of SLC6A4. We then genotyped the 5-HTT-linked polymorphic region (5-HTTLPR) and investigated the relationship among 5-HTTLPR, DNA methylation, and amygdala volume using brain imaging data. We found that patients harboring low-activity 5-HTTLPR alleles showed hypermethylation and they showed a negative correlation between DNA methylation levels and left amygdala volumes. These results suggest that hypermethylation of the CpG site in SLC6A4 is involved in the pathophysiology of SZ, especially in male patients harboring low-activity 5-HTTLPR alleles.

genetics↗

bioRxiv2019

Structural basis for ligand-induced inactivation of protein tyrosine receptor type Z (PTPRZ): Physiological relevance of head-to-toe RPTP dimerization

Protein tyrosine phosphatase receptor type Z (PTPRZ) has two receptor isoforms (PTPRZ-A and -B) containing tandem PTP-D1 and -D2 domains intracellularly, with only D1 being active. Pleiotrophin (PTN) binding to the extracellular region of PTPRZ leads to the inactivation of PTPase, thereby inducing oligodendrocyte precursor cell (OPC) differentiation and myelination in the CNS. However, the mechanisms responsible for the ligand-induced inactivation of PTPRZ remain unclear. We herein revealed that the crystal structure of the intracellular region of PTPRZ (PTPRZ-ICR) showed the \"head-to-toe\"-type dimer conformation, with D2 masking the catalytic site of D1. Mass spectrometry (MS) revealed that PTPRZ-ICR proteins remained in monomer-dimer equilibrium in aqueous solution, and a substrate-derived inhibitory peptide or competitive inhibitor (SCB4380) specifically bound to the monomer form in a 1:1 stoichiometric ratio, supporting the \"head-to-toe dimerization\" model for inactivation. A D2 deletion ({Delta}D2) or dimer interface mutation (DDKK) disrupted dimer formation, while the binding of SCB4380 was maintained. Similar to wild-type PTPRZ-B, monomer-biased PTPRZ-B-{Delta}D2 and PTPRZ-B-DDKK mutants efficiently dephosphorylated p190RhoGAP at Tyr-1105 when co-expressed in BHK-21 cells. The catalytic activities of these mutants were not suppressed by a treatment with PTN, but were inhibited by the cell-permeable PTPase inhibitor NAZ2329. The PTN treatment did not enhance OPC differentiation in primary cultured glial cells prepared from {Delta}D2 or catalytically-inactive CS mutant knock-in mice. Our results indicate that PTN-induced PTPRZ inactivation is attained by dimer formation of the intracellular tandem PTP domains in the head-to-toe configuration, which is physiologically relevant to the control of OPC differentiation in vivo.

biochemistry↗

bioRxiv2018

Functionalized mesoporous silica nanoparticles for innovative boron-neutron capture therapy of resistant cancers

Treatment resistance, relapse and metastasis remain critical issues in some challenging cancers, such as chondrosarcomas. Boron-neutron Capture Therapy (BNCT) is a targeted radiation therapy modality that relies on the ability of boron atoms to capture low energy neutrons, yielding high linear energy transfer alpha particles. We have developed an innovative boron-delivery system for BNCT, composed of multifunctional fluorescent mesoporous silica nanoparticles (B-MSNs), grafted with an activatable cell penetrating peptide (ACPP) for improved penetration in tumors and with Gadolinium for magnetic resonance imaging (MRI) in vivo. Chondrosarcoma cells were exposed in vitro to an epithermal neutron beam after B-MSNs administration. BNCT beam exposure successfully induced DNA damage and cell death, including in radio-resistant ALDH+ cancer stem cells (CSCs), suggesting that BNCT using this system might be a suitable treatment modality for chondrosarcoma or other hard-to-treat cancers.

cancer biology↗