ZOLD Calpain inhibitor and ibudilast rescue β cell functions in a cellular model of Wolfram syndrome

Publication: PNAS.org | Publication Date: July 21, 2020

Authors: Lien D. Nguyen, Tom T. Fischer, Damien Abreu, Alfredo Arroyo, Fumihiko Urano, and Barbara E. Ehrlich

Significance

Wolfram syndrome is a rare multisystem disease characterized by diabetes insipidus, diabetes mellitus, optic nerve atrophy, and deafness (DIDMOAD). It is primarily caused by mutations in the Wolfram syndrome 1 gene, WFS1. As a monogenetic disorder, Wolfram syndrome is a model for diabetes and neurodegeneration. There is no effective treatment for this invariably fatal disease. Here we characterize WFS1 as a regulator of calcium homeostasis and subsequently target calcium signaling to reverse deficits in a cellular model of Wolfram syndrome.

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Characterization of an induced pluripotent stem cell line (IMBPASi001-A) derived from fibroblasts of a patient affected by Wolfram Syndrome

Publication: ScienceDirect.com | Publication Date: July 2020

Authors: Dawid P.Grzela, Beata Marciniak, Lukasz Pulaski

Abstract

Wolfram Syndrome is a rare, autosomal recessive genetic disorder with clinical symptoms appearing in early childhood. Here, we report a generation of iPSCs from fibroblasts of a patient affected by this disease. Read more

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A soluble endoplasmic reticulum factor as regenerative therapy for Wolfram syndrome

Publication: Nature.com | Publication Date: May 4, 2020

Authors: Jana Mahadevan, Shuntaro Morikawa, Takuya Yagi, Damien Abreu, Simin Lu, Kohsuke Kanekura, Cris M. Brown & Fumihiko Urano

Abstract

Endoplasmic reticulum (ER) stress-mediated cell death is an emerging target for human chronic disorders, including neurodegeneration and diabetes. However, there is currently no treatment for preventing ER stress-mediated cell death. Here, we show that mesencephalic astrocyte-derived neurotrophic factor (MANF), a neurotrophic factor secreted from ER stressed cells, prevents ER stress-mediated β cell death and enhances β cell proliferation in cell and mouse models of Wolfram syndrome, a prototype of ER disorders. Read more

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ZOLD Gene-edited human stem cell–derived β cells from a patient with monogenic diabetes reverse preexisting diabetes in mice

Publication: Science Translational Medicine | Publication Date: April 22, 2020

Authors: Kristina G. Maxwell, Punn Augsornworawat, Leonardo Velazco-Cruz, Michelle H. Kim, Rie Asada, Nathaniel J. Hogrebe, Shuntaro Morikawa, Fumihiko Urano, Jeffrey R. Millman

Repaired β cells for replacement therapy

Wolfram syndrome is a recessive genetic disease caused by mutations in WFS1 (Wolfram syndrome 1) and can present with a multitude of symptoms including diabetes, optic atrophy, and neurological problems. There is currently no cure and patients are managed with symptomatic treatment. Maxwell et al. corrected a WFS1 pathogenic variant in patient fibroblast-derived induced pluripotent stem cells (iPSCs) that they then differentiated to pancreatic β cells. The gene-corrected β cells showed improved glucose-stimulated insulin secretion and reversed hyperglycemia for 6 months after their transplantation into diabetic mice. This study may open up the possibility of autologous β cell transplants for patients with Wolfram syndrome.

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ZOLD Neuronal Calcium Sensor 1 (NCS1) as a Potential Drug Target for Treatment of Wolfram Syndrome

Publication: The Faseb Journal | Publication Date: April 15, 2020

Authors: Tom T. Fischer, Lien D. Nguyen, Barbara E. Ehrlich

Abstract

Wolfram syndrome (WS) is an orphan, autosomal recessive neuroendocrinological disease that affects approximately 1 in 500,000 people worldwide. Patients develop diabetes mellitus, diabetes insipidus, optical atrophy, and hearing loss and usually die in their 30s. The majority of cases are attributed to mutations in a single gene, WFS1, which encodes for the protein wolframin. Despite the known genetic cause, there is currently no direct treatment for WS. This lack of therapy is because the regular functions of wolframin, and the pathophysiological consequences following the loss of intact WFS1, remain elusive. Here, we further examined the function of WFS1 in the context of glucose toxicity, to address the earliest diagnosed symptom of WS which is the onset of diabetes mellitus near age 6. Based on a recent study, we aimed to show that WFS1 interaction with a calcium binding protein, neuronal calcium sensor 1 (NCS1), is important for its normal functions. NCS1 is known to regulate exocytosis, promote cell survival, and maintain calcium homeostasis. We showed that knocking out WFS1 in rat insulinoma (INS1) cells resulted in increased baseline calcium, reduced ATP‐evoked inositol‐trisphosphate receptor (InsP3R)‐dependent calcium response, reduced phospho‐Akt (Ser473), and increased vulnerability to high glucose treatment. Furthermore, both INS1 control (CTRL) and WFS1 knockout (KO) cells showed increased NCS1 mRNA following high glucose treatment. However, only the CTRL cells showed increased NCS1 protein expression, whereas WFS1 KO cells showed decreased NCS1 expression. These results suggest that NCS1‐WFS1 interaction protects NCS1 from degradation, potentially by the calcium‐dependent protease calpain. Lastly, we showed that overexpression of NCS1, or treatment with a putative NCS1‐binding drug, rescued the deficits observed in WFS1 KO cells. Overall, we demonstrated a physiological function of the WFS1‐NCS1 interaction and that protecting NCS1 levels can ameliorate the deficits caused by loss of WFS1. These findings will facilitate the discovery of drugs that can prevent or reduce the symptoms of WS.

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ZOLD Effect of 4-phenylbutyrate and valproate on dominant mutations of WFS1 gene in Wolfram syndrome

Publication: Springer Link | Publication Date: March 26, 2020

Authors: K. Batjargal, T. Tajima, E. F. Jimbo & T. Yamagata

Abstract

Purpose

Wolfram syndrome (WS) is a rare disorder caused by mutations in WFS1 that is characterized by diabetes mellitus, optic atrophy, sensorineural deafness, diabetes insipidus, and neurodegeneration. This disease is usually inherited as an autosomal recessive trait, but an autosomal dominant form has been reported. WFS1 encodes a transmembrane protein, which is a maintenance component of endoplasmic homeostasis. These dominant mutations were thought to increase endoplasmic reticulum (ER) stress. Recent studies suggest that 4-phenylbutyrate (PBA) and valproate (VPA) reduce ER stress. The objective of this study was to analyze the effect of PBA and VPA on dominant WFS1 mutants in vitro.

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Calcium mishandling in absence of primary mitochondrial dysfunction drives cellular pathology in Wolfram Syndrome

Publication: Nature.com | Publication Date: March 16, 2020

Authors: Chiara La Morgia, Alessandra Maresca, Giulia Amore, Laura Ludovica Gramegna, Michele Carbonelli, Emanuela Scimonelli, Alberto Danese, Simone Patergnani, Leonardo Caporali, Francesca Tagliavini, Valentina Del Dotto, Mariantonietta Capristo, Federico Sadun, Piero Barboni, Giacomo Savini, Stefania Evangelisti, Claudio Bianchini, Maria Lucia Valentino, Rocco Liguori, Caterina Tonon, Carlotta Giorgi, Paolo Pinton, Raffaele Lodi & Valerio Carelli

Abstract

Wolfram syndrome (WS) is a recessive multisystem disorder defined by the association of diabetes mellitus and optic atrophy, reminiscent of mitochondrial diseases. The role played by mitochondria remains elusive, with contradictory results on the occurrence of mitochondrial dysfunction. Read more

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Taste and smell function in Wolfram syndrome

Publication: Orphanet Journal of Rare Diseases | Publication Date: February 22, 2020

Authors: Raul Alfaro, Tasha Doty, Anagha Narayanan, Heather Lugar, Tamara Hershey & M. Yanina Pepino

Abstract

Background: Wolfram syndrome is a rare genetic disease characterized by insulin-dependent diabetes, optic nerve atrophy, sensorineural hearing loss and neurodegeneration. Read more

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ZOLD Wolfram syndrome 1 gene regulates pathways maintaining beta-cell health and survival

Publication: Nature.com | Publication Date: February 14, 2020

Authors: Damien Abreu, Rie Asada, John M. P. Revilla, Zeno Lavagnino, Kelly Kries, David W. Piston & Fumihiko Urano

Abstract

Wolfram Syndrome 1 (WFS1) protein is an endoplasmic reticulum (ER) factor whose deficiency results in juvenile-onset diabetes secondary to cellular dysfunction and apoptosis. The mechanisms guiding β-cell outcomes secondary to WFS1 function, however, remain unclear. Here, we show that WFS1 preserves normal β-cell physiology by promoting insulin biosynthesis and negatively regulating ER stress. Depletion of Wfs1 in vivo and in vitro causes functional defects in glucose-stimulated insulin secretion and insulin content, triggering Chop-mediated apoptotic pathways. Genetic proof of concept studies coupled with RNA-seq reveal that increasing WFS1 confers a functional and a survival advantage to β-cells under ER stress by increasing insulin gene expression and downregulating the Chop-Trib3 axis, thereby activating Akt pathways. Remarkably, WFS1 and INS levels are reduced in type-2 diabetic (T2DM) islets, suggesting that WFS1 may contribute to T2DM β-cell pathology. Taken together, this work reveals essential pathways regulated by WFS1 to control β-cell survival and function primarily through preservation of ER homeostasis.

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High Prevalence of a Monogenic Cause in Han Chinese Diagnosed With Type 1 Diabetes, Partly Driven by Nonsyndromic Recessive WFS1 Mutations

Publication: American Diabetes Association | Publication Date: January 2020

Authors: Meihang Li, Sihua Wang, Kuanfeng Xu, Yang Chen, Qi Fu, Yong Gu, Yun Shi, Mei Zhang, Min Sun, Heng Chen, Xiuqun Han, Yangxi Li, Zhoukai Tang, Lejing Cai, Zhiqiang Li, Yongyong Shi, Tao Yang and Constantin Polychronakos

Abstract

It is estimated that ∼1% of European ancestry patients clinically diagnosed with type 1 diabetes (T1D) actually have monogenic forms of the disease. Because of the much lower incidence of true T1D in East Asians, we hypothesized that the percentage would be much higher. Read more

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