Biology subjects

Miyahara, H.

Publications and source records attributed to Miyahara, H..

5 recordsLinked to original sources

bioRxiv2023

Biallelic variants in LARS1 induce steatosis in developing zebrafish liver via enhanced autophagy

Acute liver failure is a life-threatening condition during infancy. Biallelic pathogenic variants in LARS1 cause infantile liver failure syndrome type 1 (ILFS1), which is characterized by acute hepatic failure in infants. LARS functions as a protein associated with mTORC1 and plays a crucial role in amino acid-triggered mTORC1 activation and autophagy regulation. A previous study demonstrated that larsb-knockout zebrafish show a condition resembling ILFS. However, a comprehensive analysis of larsb-knockout zebrafish has not yet been performed because of early mortality. We herein generated a long-term viable zebrafish model carrying a LARS1 variant identified in an ILFS1 patient (larsb-I451F zebrafish) and analyzed the pathogenesis of the affected liver of ILFS1. Hepatic dysfunction is most prominent in ILFS1 patients during infancy; correspondingly, the larsb-I451F zebrafish manifested hepatic anomalies during the developmental stages. The larsb-I451F zebrafish demonstrates augmented lipid accumulation within the liver under autophagy activation. Inhibition of DGAT1, which converts fatty acids to triacylglycerols, improved lipid droplets in the liver of larsb-I451F zebrafish. Notably, treatment with an autophagy inhibitor ameliorated hepatic lipid accumulation in this model. Our findings suggested that enhanced autophagy caused by biallelic LARS1 variants contributes to ILFS1-associated hepatic dysfunction. Furthermore, the larsb-I451F zebrafish model, which has a prolonged survival rate compared to the larsb-knockout model, highlights its potential utility as a tool for investigating the pathophysiology of ILFS1-associated liver dysfunction. Author SummaryInfantile liver failure (ALF) is a rare but life-threatening condition primarily caused by various genetic and infectious factors during infancy. Comprehensive research into its causes is crucial for treatment decisions, including liver transplantation and supportive interventions. While specific therapies exist for some conditions, a significant proportion of infant ALF cases remains unresolved. Recent advances in genetic sequencing have identified congenital disorders, particularly involving the LARS1 gene, as contributors to ALF. LARS1 is essential for regulating processes related to amino acids and autophagy. To better understand this condition, we created a zebrafish model carrying specific LARS1 gene variants seen in ALF patients. These zebrafish displayed liver abnormalities similar to those observed in infants with ALF. Our study revealed that enhanced autophagy, triggered by biallelic LARS1 variants, plays a significant role in liver dysfunction associated with ALF. Notably, inhibiting specific enzymes involved in fat metabolism and autophagy showed promising results in reducing hepatic lipid accumulation in our zebrafish model. This research provides insights that may lead to improved understanding and potential treatments for this devastating condition.

cell biology↗

bioRxiv2023

Identical tau filaments in subacute sclerosing panencephalitis and chronic traumatic encephalopathy

Subacute sclerosing panencephalitis (SSPE) occurs in some individuals after measles infection, following a symptom-free period of several years. It resembles chronic traumatic encephalopathy (CTE), which happens after repetitive head impacts or exposure to blast waves, following a symptom-free period. As in CTE, when present, the neurofibrillary changes of SSPE are concentrated in superficial cortical layers. Here we used electron cryo-microscopy of tau filaments from two cases of SSPE to show that the tau folds of SSPE and CTE are identical. Two types of filaments were each made of two identical protofilaments with an extra density in the {beta}-helix region. Like in CTE, the vast majority of tau filaments were Type I, with a minority of Type II filaments. These findings suggest that the CTE tau fold can be caused by different environmental insults, which may be linked by inflammatory changes.

neuroscience↗

bioRxiv2021

Macrophages in the reticuloendothelial system inhibit the propagation phase of mouse apolipoprotein A-II amyloidosis

Amyloidosis refers to a group of degenerative diseases that are characterized by the deposition of misfolded protein fibrils in various organs. Deposited amyloid may be removed by a phagocyte-dependent innate immune system; however, the precise mechanisms during disease progression remain unclear. We herein investigated the properties of macrophages that contribute to amyloid degradation and disease progression using transmissible apolipoprotein A-II amyloidosis model mice. Intravenously injected AApoAII amyloid was efficiently engulfed by reticuloendothelial macrophages in the liver and spleen and disappeared by 24 h. While cultured murine macrophages degraded AApoAII via the endosomal-lysosomal pathway, AApoAII fibrils reduced cell viability and phagocytic capacity. Furthermore, the depletion of reticuloendothelial macrophages prior to the induction of AApoAII markedly increased hepatic and splenic AApoAII deposition. These results highlight the physiological role of reticuloendothelial macrophages against inter-individual amyloid propagation and suggest the maintenance of phagocytic integrity as a therapeutic strategy to inhibit disease progression.

molecular biology↗

bioRxiv2020

Curcumin promotes progression of AApoAII amyloidosis and peroxisome proliferation in mice by activating the PPARα signaling pathway

Curcumin is a polyphenol compound that exhibits multiple physiological activities. To elucidate the mechanisms by which curcumin affects systemic amyloidosis, we investigated amyloid deposition and molecular changes in a mouse model of amyloid apolipoprotein A-II (AApoAII) amyloidosis, in which mice were fed a curcumin-supplemented diet. Curcumin supplementation for 12 weeks significantly increased AApoAII amyloid deposition relative to controls, especially in the liver and spleen. Liver weights and plasma ApoA-II and high-density lipoprotein concentrations were significantly elevated in curcumin-supplemented groups. RNA-sequence analysis revealed that curcumin intake affected hepatic lipid metabolism via the peroxisome proliferator-activated receptor (PPAR) pathway, especially PPAR activation, resulting in increased Apoa2 mRNA expression. The increase in liver weights was due to activation of PPAR and peroxisome proliferation. Taken together, these results demonstrate that curcumin is a PPAR activator and may affect expression levels of proteins involved in amyloid deposition to influence amyloidosis and metabolism in a complex manner.

molecular biology↗

bioRxiv2020

State-space Modeling Clarifies Productivity Regime Shifts of Japanese Flying Squid

Regime shifts of climatic and environmental conditions potentially affect productivity of fisheries resources, posing challenging issues to stock management. The stocks of the Japanese flying squid (Todarodes pacificus) are suspected to suffer from regime shifts, but their detection is difficult and possibly doubtful because the nature of short-lived species readily makes the effect of regime shifts confounded with observation errors. Here we developed a new state-space assessment model to evaluate the influence of regime shifts on spawner-recruitment relationship of the Japanese flying squid. The model simultaneously estimates the population dynamics of multiple stocks that could share some life history parameters, making parameter inference stable. We demonstrate that two-time regime shifts of productivity around 1991 and 2015 caused two-to three-fold changes of maximum sustinabile yields. The model with regime shifts clarifies the relationship between fishing pressure and spawner abudance that is difficult to detect in a model with no regime shift. The state-space approach will be a promising tool to accurately assess stock status by separating recruitment process from observation errors and contribute tothe management of marine biological resources sensitive to regime shifts.

ecology↗