Biology subjects

Tomiyama, T.

Publications and source records attributed to Tomiyama, T..

4 recordsLinked to original sources

bioRxiv2026

Mirror-image mRNA display uncovers isoform-selective D-peptide macrocycles targeting a cryptic KRAS pocket

Activating KRAS mutations drive millions of cancers diagnosed worldwide,1 yet for decades this oncoprotein was deemed "undruggable", reflecting the challenge of discovering molecules capable of perturbing its complex biological functions, and of translating these discoveries into effective cancer therapeutics.2 Recent advances propelled by innovative screening have identified diverse modalities that bind at or near the switch-II pocket (SII-P) of RAS proteins, including molecular glues,3 macrocyclic peptides,4 fragment-derived small molecules,5 and approved therapies that covalently target KRASG12C.6,7 Unfortunately, resistance to approved therapies has emerged,8,9 highlighting the need for molecules that engage new or underexploited binding sites on RAS oncoproteins with mechanisms complementary to established SII-P inhibitors.10,11 Here we show that mirror-image mRNA display12 enabled the discovery of all-D macrocyclic peptide ligands targeting a cryptic RAS back pocket (CRB-P).13 These ligands engage KRAS(OFF) and KRAS(ON) with equal affinity, exploit a single-residue difference among isoforms to bind KRAS selectively, and successfully inhibit oncogenic signaling in KRAS-mutant cells through a mechanism distinct from SII-P binders. Mirror-image screening directly afforded nanomolar peptide ligands stable toward cellular proteolysis and delivered probes targeting distinct epitopes not accessible by homochiral peptide-display methods. Together, these findings establish the CRB-P as a specifically druggable and mechanistically differentiated site on KRAS with potential for combination with emerging RAS-targeting therapies and substantiate mirror-image mRNA display as a strategy for discovering stable all-D macrocyclic peptides targeting previously inaccessible epitopes on challenging targets.

cancer biology↗

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↗

bioRxiv2024

Simply crushed Zizyphi spinosi semen prevents neurodegenerative diseases and reverses age-related cognitive decline in mice

Neurodegenerative diseases are age-related disorders characterized by the cerebral accumulation of amyloidogenic proteins, and cellular senescence underlies their pathogenesis. Thus, it is necessary for preventing these diseases to remove toxic proteins, repair damaged neurons, and suppress cellular senescence. As a source for such prophylactic agents, we selected Zizyphi spinosi semen (ZSS), a medicinal herb used in traditional Chinese medicine. ZSS hot water extract ameliorated A{beta} and tau pathology and cognitive impairment in mouse models of Alzheimers disease and frontotemporal dementia. Non-extracted ZSS simple crush powder showed stronger effects than the extract and improved -synuclein pathology and cognitive/motor function in Parkinsons disease model mice. Furthermore, when administered to normal aged mice, the ZSS powder suppressed cellular senescence, reduced DNA oxidation, promoted brain-derived neurotrophic factor expression and neurogenesis, and enhanced cognition to levels similar to those in young mice. The quantity of known active ingredients of ZSS, jujuboside A, jujuboside B, and spinosin, was not proportional to the nootropic activity of ZSS. These results suggest that ZSS simple crush powder is a promising dietary material for the prevention of neurodegenerative diseases and brain aging. Impact statement Non-extracted simple crush powder of Zizyphi spinosi semen has not only disease-preventing effects but also brain-rejuvenating effects in mice.

neuroscience↗

bioRxiv2018

Ectopic expression induces abnormal somatodendritic distribution of tau in the mouse brain

Tau is a microtubule-associated protein that is localized to the axon. In Alzheimers disease, the distribution of tau undergoes a remarkable alteration, leading to the formation of tau inclusions in the somatodendritic compartment. To investigate how this mis-localization occurs, we recently developed immunohistochemical techniques that can separately detect endogenous mouse and exogenous human tau with high sensitivity, which allows us to visualize not only the pathological but pre-aggregated tau in mouse brain tissues of both sex. In tau transgenic mouse brains, exogenous human tau was abundant in dendrites and somata even in the presymptomatic period, whereas the axonal localization of endogenous mouse tau was unaffected. In stark contrast, exogenous tau was properly localized to the axon in human tau knock-in mice. We tracked this difference to the temporal expression patterns of tau. Tau mRNA was continuously expressed in the transgenic mice, whereas endogenous tau and exogenous tau in the knock-in mice exhibited high expression levels during the neonatal period and strong suppression into the adulthood. These results indicated the uncontrolled expression of exogenous tau beyond the developmental period as a cause of mis-localization in the transgenic mice. Super-resolution microscopic and biochemical analyses also indicated that the interaction between microtubules and exogenous tau was indeed impaired in the tau transgenic mice. Thus, the ectopic expression of tau may be critical for its somatodendritic mis-localization, a key step of the tauopathy.\n\nSignificance StatementSomatodendritic localization of tau may be an early step leading to the neuronal degeneration in tauopathies. However, the mechanisms of the normal axonal distribution of tau and the mis-localization of pathological tau remain obscure. Our immunohistochemical and biochemical analyses demonstrated that the endogenous mouse tau is transiently expressed in neonatal brains, that exogenous human tau expressed corresponding to such tau expression profile can distribute into the axon, and that the constitutive expression of tau into adulthood (ex. human tau in Tg mice) results in abnormal somatodendritic localization. Thus, the expression profile of tau is tightly associated with the localization of tau, and the ectopic expression of tau in matured neurons may be involved in the pathogenesis of tauopathy.

neuroscience↗