Showing papers by "Fumihiko Urano published in 2016"
TL;DR: The natural history and etiology of Wolfram syndrome is described, recommendations for diagnosis and clinical management are provided, and new treatments for the syndrome are introduced.
Abstract: Wolfram syndrome is a rare genetic disorder characterized by juvenile-onset diabetes mellitus, diabetes insipidus, optic nerve atrophy, hearing loss, and neurodegeneration. Although there are currently no effective treatments that can delay or reverse the progression of Wolfram syndrome, the use of careful clinical monitoring and supportive care can help relieve the suffering of patients and improve their quality of life. The prognosis of this syndrome is currently poor, and many patients die prematurely with severe neurological disabilities, raising the urgency for developing novel treatments for Wolfram syndrome. In this article, we describe natural history and etiology, provide recommendations for diagnosis and clinical management, and introduce new treatments for Wolfram syndrome.
185 citations
TL;DR: It is demonstrated that impaired protein translation mediated by poly-PR and poly-GR peptides plays a role in neurotoxicity and revealed that the pathways altered by the poly-dipeptides-mRNA complexes are potential therapeutic targets for treatment of C9orf72 FTD/ALS.
Abstract: The expansion of the GGGGCC hexanucleotide repeat in the non-coding region of the Chromosome 9 open-reading frame 72 (C9orf72) gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This genetic alteration leads to the accumulation of five types of poly-dipeptides translated from the GGGGCC hexanucleotide repeat. Among these, poly-proline-arginine (poly-PR) and poly-glycine-arginine (poly-GR) peptides are known to be neurotoxic. However, the mechanisms of neurotoxicity associated with these poly-dipeptides are not clear. A proteomics approach identified a number of interacting proteins with poly-PR peptide, including mRNA-binding proteins, ribosomal proteins, translation initiation factors and translation elongation factors. Immunostaining of brain sections from patients with C9orf72 ALS showed that poly-GR was colocalized with a mRNA-binding protein, hnRNPA1. In vitro translation assays showed that poly-PR and poly-GR peptides made insoluble complexes with mRNA, restrained the access of translation factors to mRNA, and blocked protein translation. Our results demonstrate that impaired protein translation mediated by poly-PR and poly-GR peptides plays a role in neurotoxicity and reveal that the pathways altered by the poly-dipeptides-mRNA complexes are potential therapeutic targets for treatment of C9orf72 FTD/ALS.
133 citations
TL;DR: It is found that radiation can induce ER stress and downstream signaling associated with the ERSR, and activation of ATF6 contributes to the radiation-induced upregulation of glucose regulated protein 78 (GRP78) and NOTCH1.
Abstract: Therapeutic resistance is a major barrier to improvement of outcomes for patients with glioblastoma. The endoplasmic reticulum stress response (ERSR) has been identified as a contributor to chemoresistance in glioblastoma; however the contributions of the ERSR to radioresistance have not been characterized. In this study we found that radiation can induce ER stress and downstream signaling associated with the ERSR. Induction of ER stress appears to be linked to changes in ROS balance secondary to irradiation. Furthermore, we observed global induction of genes downstream of the ERSR in irradiated glioblastoma. Knockdown of ATF6, a regulator of the ERSR, was sufficient to enhance radiation induced cell death. Also, we found that activation of ATF6 contributes to the radiation-induced upregulation of glucose regulated protein 78 (GRP78) and NOTCH1. Our results reveal ATF6 as a potential therapeutic target to enhance the efficacy of radiation therapy.
82 citations
TL;DR: Islets from mice lacking Rpl13a snoRNAs demonstrated blunted oxidative stress responses, and these mice were protected against diabetogenic stimuli that cause oxidative stress damage to islets, illuminates a previously unrecognized role for sno RNAs in metabolic regulation.
Abstract: Small nucleolar RNAs (snoRNAs) are non-coding RNAs that form ribonucleoproteins to guide covalent modifications of ribosomal and small nuclear RNAs in the nucleus. Recent studies have also uncovered additional non-canonical roles for snoRNAs. However, the physiological contributions of these small RNAs are largely unknown. Here, we selectively deleted four snoRNAs encoded within the introns of the ribosomal protein L13a (Rpl13a) locus in a mouse model. Loss of Rpl13a snoRNAs altered mitochondrial metabolism and lowered reactive oxygen species tone, leading to increased glucose-stimulated insulin secretion from pancreatic islets and enhanced systemic glucose tolerance. Islets from mice lacking Rpl13a snoRNAs demonstrated blunted oxidative stress responses. Furthermore, these mice were protected against diabetogenic stimuli that cause oxidative stress damage to islets. Our study illuminates a previously unrecognized role for snoRNAs in metabolic regulation.
61 citations
TL;DR: A review of recent findings on ER stress in β cells and development of type 1 diabetes is highlighted and potential new treatments targeting the ER are introduced to combat this disorder.
50 citations
École normale supérieure de Lyon1, University of Edinburgh2, French Institute of Health and Medical Research3, University of Chile4, University of Paris5, PSL Research University6, ANSES7, University of Coimbra8, New York University9, Rockefeller University10, Washington University in St. Louis11, University of Rennes12, Pierre-and-Marie-Curie University13, Technion – Israel Institute of Technology14, University of Massachusetts Amherst15, Discovery Institute16, Harvard University17
TL;DR: The impact of adaptive stress responses stimulated in diverse human neuropathologies including Parkinson׳s disease, Wolfram syndrome, brain ischemia, and brain cancer are discussed and how these responses and the molecular pathways they recruit might be exploited for therapeutic gain are examined.
45 citations
TL;DR: Mesencephalic astrocyte-derived neurotrophic factor can potentially serve as a urine diagnostic or prognostic biomarker in ER stress-related kidney diseases to help stratify disease risk, predict disease progression, monitor treatment response, and identify subgroups of patients who can be treated with ER stress modulators in a highly targeted manner.
Abstract: Endoplasmic reticulum (ER) stress and disrupted proteostasis contribute to the pathogenesis of a variety of glomerular and tubular diseases. Thus, it is imperative to develop noninvasive biomarkers for detecting ER stress in podocytes or tubular cells in the incipient stage of disease, when a kidney biopsy is not yet clinically indicated. Mesencephalic astrocyte-derived neurotrophic factor (MANF) localizes to the ER lumen and is secreted in response to ER stress in several cell types. Here, using mouse models of human nephrotic syndrome caused by mutant laminin β2 protein-induced podocyte ER stress and AKI triggered by tunicamycin- or ischemia-reperfusion-induced tubular ER stress, we examined MANF as a potential urine biomarker for detecting ER stress in podocytes or renal tubular cells. ER stress upregulated MANF expression in podocytes and tubular cells. Notably, urinary MANF excretion concurrent with podocyte or tubular cell ER stress preceded clinical or histologic manifestations of the corresponding disease. Thus, MANF can potentially serve as a urine diagnostic or prognostic biomarker in ER stress-related kidney diseases to help stratify disease risk, predict disease progression, monitor treatment response, and identify subgroups of patients who can be treated with ER stress modulators in a highly targeted manner.
43 citations
TL;DR: White matter microstructure and regional volumes were measured using magnetic resonance imaging in children and young adults with Wolfram syndrome and healthy and diabetic controls and correlations were found between key brain findings and overall neurological symptoms.
Abstract: Wolfram syndrome is a rare autosomal recessive genetic disease characterized by insulin dependent diabetes and vision, hearing and brain abnormalities which generally emerge in childhood. Mutations in the WFS1 gene predispose cells to endoplasmic reticulum stress-mediated apoptosis and may induce myelin degradation in neuronal cell models. However, in vivo evidence of this phenomenon in humans is lacking. White matter microstructure and regional volumes were measured using magnetic resonance imaging in children and young adults with Wolfram syndrome (n = 21) and healthy and diabetic controls (n = 50). Wolfram patients had lower fractional anisotropy and higher radial diffusivity in major white matter tracts and lower volume in the basilar (ventral) pons, cerebellar white matter and visual cortex. Correlations were found between key brain findings and overall neurological symptoms. This pattern of findings suggests that reduction in myelin is a primary neuropathological feature of Wolfram syndrome. Endoplasmic reticulum stress-related dysfunction in Wolfram syndrome may interact with the development of myelin or promote degeneration of myelin during the progression of the disease. These measures may provide objective indices of Wolfram syndrome pathophysiology that will be useful in unraveling the underlying mechanisms and in testing the impact of treatments on the brain.
31 citations
TL;DR: In mouse models, cell lines, and ex vivo islets, it is shown that disruption of HNF4α caused decreased expression of XBP1 and reduced cellular ER networks, and that diminished X BP1 and/or H NF4α in β-cells led to impaired ER Ca2+ homeostasis.
26 citations
19 Aug 2016
TL;DR: A 12-year-old girl referred to pediatric endocrine clinic for evaluation of new onset diabetes was found to have an elevated random glucose in her pediatrician’s office 3 months before and was started on metformin and lisinopril prior to the referral.
Abstract: Background Insulin resistance occurs in a variety of common endocrine disorders including obesity, type 2 diabetes, polycystic ovarian syndrome, and metabolic syndrome. Additionally, rare syndromes exist that result in extreme insulin resistance. These conditions help contribute to our knowledge of the mechanisms of insulin signaling and resistance. Case 12-year-old girl referred to pediatric endocrine clinic for evaluation of new onset diabetes. She was found to have an elevated random glucose in her pediatrician’s office 3 months before. Subsequently she was started on metformin and lisinopril prior to the referral. • Birth weight: 6lb 7oz (2920 g) • Obese since kindergarten age • Extreme weight gain in the last 2 years • Nearly continuous growth spurt • Now having difficulty fitting into her clothes • Premenarchal