Restoration of the defect in radial glial fiber migration and cortical plate organization in a brain organoid model of Fukuyama muscular dystrophy

Taniguchi‐Ikeda, Mariko; Koyanagi-Aoi, Michiyo; Maruyama, Tatsuo; Takaori, Toru; Hosoya, Akiko; Tezuka, Hiroyuki; Nagase, Shotaro; Ishihara, Takuma; Kadoshima, Taisuke; Muguruma, Keiko; Ishigaki, Keiko; Sakurai, Hiroyuki; Mizoguchi, Akira; Novitch, Bennett G.; Toda, Tatsushi; Watanabe, Momoko; Aoi, Takashi

doi:10.1016/j.isci.2021.103140

Cited by 7 publications

(6 citation statements)

References 36 publications

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“…Severe brain malformation of Emx1-fukutin-cKO mouse is prevented by delivery of fukutin into the brain at E12.5 [58]. In a brain organoid model of FCMD, abnormal radial glial fiber migration is restored by Mannan-007 [59]. It is not easy to overcome a lot of difficulties to apply new molecular or gene-based therapies, especially to fetuses.…”

Section: Morphological Alteration Of Neuroblastoma Cells (Imr32) Afte...mentioning

confidence: 99%

Perspective Chapter: Multiple Functions of Fukutin, the Gene Responsible for Fukuyama Congenital Muscular Dystrophy, Especially in the Central Nervous System

Yamamoto¹,

Okamura²,

Tsukui³

et al. 2023

Potential Therapeutic Strategies for Muscular Dystrophy

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Fukuyama congenital muscular dystrophy (FCMD), accompanying central nervous system (CNS) and ocular anomalies, is the second common muscular dystrophy in Japan, and the responsible gene is fukutin. The lesions are mainly caused by fragile basement membrane/cell membrane due to hypoglycosylation of α-dystroglycan (α-DG), and astrocytes play a crucial role for CNS malformation. On the other hand, since fukutin is expressed almost ubiquitously, diverse functions of fukutin, besides the glycosylation of α-DG, can be considered. As for the CNS, fukutin possibly upregulates cyclin D1 expression as a cofactor of activator protein-1 in astrocytoma. Moreover, fukutin may be involved in the phosphorylation of tau, one of the key proteins of dementia represented by Alzheimer’s disease, in glutamatergic neurons. A presynaptic function in GABAergic neurons is also suggested. Owing to the recent advances of molecular and biochemical techniques, new therapeutic strategies are under consideration, even for brain malformation, which begins to be formed during the first trimester in utero. Recovery of hypoglycosylation of α-DG supposed to be a main therapeutic target, but to know various functions and regulation systems of fukutin might be important for developing suitable therapies.

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Section: Morphological Alteration Of Neuroblastoma Cells (Imr32) Afte...mentioning

confidence: 99%

Perspective Chapter: Multiple Functions of Fukutin, the Gene Responsible for Fukuyama Congenital Muscular Dystrophy, Especially in the Central Nervous System

Yamamoto¹,

Okamura²,

Tsukui³

et al. 2023

Potential Therapeutic Strategies for Muscular Dystrophy

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“…In the developing fetal brain of DGpathy models, radial glia in the cerebrum and Bergmann glia in the cerebellum invade the subarachnoid space, which coincides with the site of basement membrane disruption and disrupts the function and localization of cells that serve as scaffolds for neuronal cell migration. It is notable that very recently, Taniguchi-Ikeda et al successfully generated three-dimensional brain organoids from FCMD patient-derived iPS cells, which recapitulated abnormal radial glial fiber migration [ 63 ]. Large myd mice, neural stem cell-selective Emx1-POMT2-cKO mice, and POMGNT1-KO mice also have structural abnormalities of the hippocampal dentate gyrus with loss of pial basement membrane [ 42 , 64 ].…”

Section: Pathological Mechanism Of Dgpathymentioning

confidence: 99%

Dystroglycanopathy: From Elucidation of Molecular and Pathological Mechanisms to Development of Treatment Methods

Kanagawa

2021

IJMS

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Dystroglycanopathy is a collective term referring to muscular dystrophies with abnormal glycosylation of dystroglycan. At least 18 causative genes of dystroglycanopathy have been identified, and its clinical symptoms are diverse, ranging from severe congenital to adult-onset limb-girdle types. Moreover, some cases are associated with symptoms involving the central nervous system. In the 2010s, the structure of sugar chains involved in the onset of dystroglycanopathy and the functions of its causative gene products began to be identified as if they were filling the missing pieces of a jigsaw puzzle. In parallel with these discoveries, various dystroglycanopathy model mice had been created, which led to the elucidation of its pathological mechanisms. Then, treatment strategies based on the molecular basis of glycosylation began to be proposed after the latter half of the 2010s. This review briefly explains the sugar chain structure of dystroglycan and the functions of the causative gene products of dystroglycanopathy, followed by introducing the pathological mechanisms involved as revealed from analyses of dystroglycanopathy model mice. Finally, potential therapeutic approaches based on the pathological mechanisms involved are discussed.

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“…In this study, we report that the aggregates of a small molecule, Mannan 007 (Mn007), specifically inhibit the DNases. Mn007 was previously identified as a potential lead compound for treating Fukuyama-type congenital muscular dystrophy (FCMD). , In the course of elucidating the therapeutic mechanism of Mn007 against FCMD, we discovered that the aggregates of Mn007 inhibited bovine pancreatic DNase I (Figure a). Thus, we examined the enzyme inhibition by the aggregates of Mn007 in detail and found that this inhibition was specific to DNase.…”

Section: Introductionmentioning

confidence: 99%

Molecular Aggregation Strategy for Inhibiting DNases

Morita,

Moriwaki,

Habe

et al. 2024

JACS Au

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This study highlights the novel potential of molecular aggregates as inhibitors of a disease-related protein. Enzyme inhibitors have been studied and developed as molecularly targeted drugs and have been applied for cancer, autoimmune diseases, and infections. In many cases, enzyme inhibitors that are used for therapeutic applications interact directly with enzymes in a molecule-to-molecule manner. We found that the aggregates of a small compound, Mn007, inhibited bovine pancreatic DNase I. Once Mn007 molecules formed aggregates, they exhibited inhibitory effects specific to DNases that require divalent metal ions. A DNase secreted by Streptococcus pyogenes causes streptococcal toxic shock syndrome (STSS). STSS is a severe infectious disease with a fatality rate exceeding 30% in patients, even in this century. S. pyogenes disrupts the human barrier system against microbial infections through the secreted DNase. Until now, the discovery/development of a DNase inhibitor has been challenging. Mn007 aggregates were found to inhibit the DNase secreted by S. pyogenes, which led to the successful suppression of S. pyogenes growth in human whole blood. To date, molecular aggregation has been outside the scope of drug discovery. The present study suggests that molecular aggregation is a vast area to be explored for drug discovery and development because aggregates of small-molecule compounds can inhibit disease-related enzymes.

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Restoration of the defect in radial glial fiber migration and cortical plate organization in a brain organoid model of Fukuyama muscular dystrophy

Cited by 7 publications

References 36 publications

Perspective Chapter: Multiple Functions of Fukutin, the Gene Responsible for Fukuyama Congenital Muscular Dystrophy, Especially in the Central Nervous System

Perspective Chapter: Multiple Functions of Fukutin, the Gene Responsible for Fukuyama Congenital Muscular Dystrophy, Especially in the Central Nervous System

Dystroglycanopathy: From Elucidation of Molecular and Pathological Mechanisms to Development of Treatment Methods

Molecular Aggregation Strategy for Inhibiting DNases

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