Biology subjects

Nishioka, K.

Publications and source records attributed to Nishioka, K..

5 recordsLinked to original sources

bioRxiv2026

Dimerisation and twist reversal of the Lewy fold in α-synuclein mutants with Parkinson's disease and dementia

Dominantly inherited missense and gene dosage mutations in SNCA, the -synuclein gene, cause familial forms of Parkinsons disease and dementia. Here we report the structures of -synuclein filaments from the brains of such individuals. Pathogenic mutations A53T and G51D in SNCA give rise to singlets and doublets of the Lewy fold with a left-handed helical twist in the absence of a peptide-like density for island A. By contrast, filaments from the non-pathogenic variant H50Q consist of singlets of the right-handed Lewy fold with a density for island A, like filaments of wild-type -synuclein. The structures of filaments from homozygous mice transgenic for human mutant A53T -synuclein (line M83) are unlike those from human brains. They are more similar to the multiple system atrophy folds than to the Lewy fold of Parkinsons disease, Parkinsons disease dementia and dementia with Lewy bodies

biophysics↗

bioRxiv2025

Amyloid-β fibrils accumulated in preeclamptic placentas suppress syncytialization of cytotrophoblasts

Cerebral deposition of fibrillar amyloid-{beta} (A{beta}) is a pathological hallmark of Alzheimers disease. While A{beta} is present in human placentas and accumulates in preeclamptic placentas characterized by poor placentation, the production and role of A{beta} in the human placenta remain unclear. Because hypoxia in mid-to-late pregnancy is a risk for preeclampsia, we found that levels of hypoxia-inducible factor 1- and {beta}-secretase (BACE-1) increased concurrently with placental A{beta} deposition in late stage preeclamptic placentas. We also found that a human cytotrophoblast (CTB) model, BeWo cells, actually produced A{beta} species, and that hypoxia increased A{beta} production and BACE-1 protein levels. A{beta}42 fibrils inhibited CTB syncytialization, a critical step in maintaining pregnancy, by inducing loss of membrane localization of cell-cell adhesion molecules. Primary human CTBs confirmed these observations. Taken together, our results suggest that increased A{beta} production in CTBs by hypoxia may lead to the formation of A{beta} fibrils, which inhibit syncytiotrophoblast formation and are detrimental to pregnancy. Thus, our results reveal the novel role of A{beta} fibrils in the pathogenesis of preeclampsia.

biochemistry↗

bioRxiv2020

Multidrug treatment with nelfinavir and cepharanthine against COVID-19

Antiviral treatments targeting the emerging coronavirus disease 2019 (COVID-19) are urgently required. We screened a panel of already-approved drugs in a cell culture model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and identified two new antiviral agents: the HIV protease inhibitor Nelfinavir and the anti-inflammatory drug Cepharanthine. In silico modeling shows Nelfinavir binds the SARS-CoV-2 main protease consistent with its inhibition of viral replication, whilst Cepharanthine inhibits viral attachment and entry into cells. Consistent with their different modes of action, in vitro assays highlight a synergistic effect of this combined treatment to limit SARS-CoV-2 proliferation. Mathematical modeling in vitro antiviral activity coupled with the known pharmacokinetics for these drugs predicts that Nelfinavir will facilitate viral clearance. Combining Nelfinavir/Cepharanthine enhanced their predicted efficacy to control viral proliferation, to ameliorate both the progression of disease and risk of transmission. In summary, this study identifies a new multidrug combination treatment for COVID-19.

microbiology↗

bioRxiv2019

Two strategies underlying the trade-off of hepatitis C virus proliferation: stay-at-home or leaving-home?

Viruses proliferate through both genome replication inside infected cells and transmission to new target cells or to new hosts. Each viral genome molecule in infected cells is used either for amplifying the intracellular genome as a template (\"stay-at-home strategy\") or for packaging into progeny virions to be released extracellularly (\"leaving-home strategy\"). The balance between these strategies is important for both initial growth and transmission of viruses. In this study, we used hepatitis C virus (HCV) as a model system to study the functions of viral genomic RNA in both RNA replication in cells and in progeny virus assembly and release. Using viral infection assays combined with mathematical modelling, we characterized the dynamics of two different HCV strains (JFH-1, a clinical isolate, and Jc1-n, a laboratory strain), which have different viral assembly and release characteristics. We found that 1.27% and 3.28% of JFH-1 and Jc1-n intracellular viral RNAs, respectively, are used for producing and releasing progeny virions. Analysis of the Malthusian parameter of the HCV genome (i.e., initial growth rate) and the number of de novo infections (i.e., initial transmissibility) suggests that the leaving-home strategy provides a higher level of initial transmission for Jc1-n, while, in contrast, the stay-at-home strategy provides a higher initial growth rate for JFH-1. Thus, theoretical-experimental analysis of viral dynamics enables us to better understand the proliferation strategies of viruses. Ours is the first study to analyze stay-leave trade-offs during the viral life cycle and their significance for viral proliferation.

evolutionary biology↗

bioRxiv2018

Growing oocyte specific transcription-dependent de novo DNA methylation at the imprinted Zrsr1-DMR

Zrsr1 is a paternally expressed imprinted gene located in the first intron of Commd1, and the Zrsr1 promoter resides in a differentially methylated region (DMR) that is maternally methylated in the oocyte. However, a mechanism for the establishment of the methylation has remained obscure. Commd1 is transcribed in the opposite direction to Zrsr1 with predominant maternal expression, especially in the adult brain. In this study, we found Commed1 transcribed through the DMR in the growing oocyte. Zrsr1-DMR methylation was abolished by the prevention of Commd1 transcription. This result indicated that methylation at the Zrsr1-DMR was transcription-dependent.

molecular biology↗