TY - JOUR
T1 - Guanabenz ameliorates disease in vanishing white matter mice in contrast to sephin1
AU - Witkamp, Diede
AU - Oudejans, Ellen
AU - Hu-A-Ng, Gino V.
AU - Hoogterp, Leoni
AU - Krzywańska, Aleksandra M.
AU - Žnidaršič, Milo
AU - Marinus, Kevin
AU - de Veij Mestdagh, Christina F.
AU - Bartelink, Imke
AU - Bugiani, Marianna
AU - van der Knaap, Marjo S.
AU - Abbink, Truus E.M.
N1 - Funding Information: This study was supported by ELA grant 2017‐02712 and ZonMW TOP grant 91211005. We thank Marcos Ross Adelman and Janneke Witvliet for their help with CatWalk; Vivi Heine, Stephanie Dooves, Timo ter Braak and Lisanne Wisse for helping with the first GBZ injections and downstream analyses of ISR mRNAs. We thank Professor Giuseppe Lauria Pinter (University of Milan, Italy) for providing guanabenz acetate and Professor Rob Henning (Rijksuniversiteit Groningen, the Netherlands) for sharing the temperature loggers. We thank Dr. Prashant Chittiboina (National Institute of Neurologic Diseases and Stroke, Bethesda, MD, USA) for sharing the AtT‐20 cell line and Professor Lee Limbird (FISK University, Nashville, TN, USA) for sharing the AtT‐20 cell line expressing α2‐AR. We thank the animal caretakers of the VU‐VUmc animal facility for mouse breeding and advice. Marjo S. van der Knaap is a member of the European reference network for rare neurological disorders (ERN‐RND), project ID 739510. Funding Information: This study was supported by ELA grant 2017-02712 and ZonMW TOP grant 91211005. We thank Marcos Ross Adelman and Janneke Witvliet for their help with CatWalk; Vivi Heine, Stephanie Dooves, Timo ter Braak and Lisanne Wisse for helping with the first GBZ injections and downstream analyses of ISR mRNAs. We thank Professor Giuseppe Lauria Pinter (University of Milan, Italy) for providing guanabenz acetate and Professor Rob Henning (Rijksuniversiteit Groningen, the Netherlands) for sharing the temperature loggers. We thank Dr. Prashant Chittiboina (National Institute of Neurologic Diseases and Stroke, Bethesda, MD, USA) for sharing the AtT-20 cell line and Professor Lee Limbird (FISK University, Nashville, TN, USA) for sharing the AtT-20 cell line expressing α2-AR. We thank the animal caretakers of the VU-VUmc animal facility for mouse breeding and advice. Marjo S. van der Knaap is a member of the European reference network for rare neurological disorders (ERN-RND), project ID 739510. Publisher Copyright: © 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
PY - 2022/8
Y1 - 2022/8
N2 - Objective: Vanishing white matter (VWM) is a leukodystrophy, characterized by stress-sensitive neurological deterioration and premature death. It is currently without curative treatment. It is caused by bi-allelic pathogenic variants in the genes encoding eukaryotic initiation factor 2B (eIF2B). eIF2B is essential for the regulation of the integrated stress response (ISR), a physiological response to cellular stress. Preclinical studies on VWM mouse models revealed that deregulated ISR is key in the pathophysiology of VWM and an effective treatment target. Guanabenz, an α2-adrenergic agonist, attenuates the ISR and has beneficial effects on VWM neuropathology. The current study aimed at elucidating guanabenz's disease-modifying potential and mechanism of action in VWM mice. Sephin1, an ISR-modulating guanabenz analog without α2-adrenergic agonistic properties, was included to separate effects on the ISR from α2-adrenergic effects. Methods: Wild-type and VWM mice were subjected to placebo, guanabenz or sephin1 treatments. Effects on clinical signs, neuropathology, and ISR deregulation were determined. Guanabenz's and sephin1's ISR-modifying effects were tested in cultured cells that expressed or lacked the α2-adrenergic receptor. Results: Guanabenz improved clinical signs, neuropathological hallmarks, and ISR regulation in VWM mice, but sephin1 did not. Guanabenz's effects on the ISR in VWM mice were not replicated in cell cultures and the contribution of α2-adrenergic effects on the deregulated ISR could therefore not be assessed. Interpretation: Guanabenz proved itself as a viable treatment option for VWM. The exact mechanism through which guanabenz exerts its ameliorating impact on VWM requires further studies. Sephin1 is not simply a guanabenz replacement without α2-adrenergic effects.
AB - Objective: Vanishing white matter (VWM) is a leukodystrophy, characterized by stress-sensitive neurological deterioration and premature death. It is currently without curative treatment. It is caused by bi-allelic pathogenic variants in the genes encoding eukaryotic initiation factor 2B (eIF2B). eIF2B is essential for the regulation of the integrated stress response (ISR), a physiological response to cellular stress. Preclinical studies on VWM mouse models revealed that deregulated ISR is key in the pathophysiology of VWM and an effective treatment target. Guanabenz, an α2-adrenergic agonist, attenuates the ISR and has beneficial effects on VWM neuropathology. The current study aimed at elucidating guanabenz's disease-modifying potential and mechanism of action in VWM mice. Sephin1, an ISR-modulating guanabenz analog without α2-adrenergic agonistic properties, was included to separate effects on the ISR from α2-adrenergic effects. Methods: Wild-type and VWM mice were subjected to placebo, guanabenz or sephin1 treatments. Effects on clinical signs, neuropathology, and ISR deregulation were determined. Guanabenz's and sephin1's ISR-modifying effects were tested in cultured cells that expressed or lacked the α2-adrenergic receptor. Results: Guanabenz improved clinical signs, neuropathological hallmarks, and ISR regulation in VWM mice, but sephin1 did not. Guanabenz's effects on the ISR in VWM mice were not replicated in cell cultures and the contribution of α2-adrenergic effects on the deregulated ISR could therefore not be assessed. Interpretation: Guanabenz proved itself as a viable treatment option for VWM. The exact mechanism through which guanabenz exerts its ameliorating impact on VWM requires further studies. Sephin1 is not simply a guanabenz replacement without α2-adrenergic effects.
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U2 - https://doi.org/10.1002/acn3.51611
DO - https://doi.org/10.1002/acn3.51611
M3 - Article
C2 - 35778832
SN - 2328-9503
VL - 9
SP - 1147
EP - 1162
JO - Annals of clinical and translational neurology
JF - Annals of clinical and translational neurology
IS - 8
ER -
