Repurposing of tamoxifen ameliorates CLN3 and CLN7 disease phenotype

EMBO Molecular Medicine

Ludger Johannes¹  Julio L Sampaio¹  Thomas Braulke²  Christian M Grimm³  Anna Scotto Rosato³  Einar K Krogsaeter³  Dominik Paquet⁴  Irene Lopez‐Fabuel⁵  Juan P Bolaños⁵  Marina Garcia‐Macia⁵  Sara E Mole⁶  Tristan McKay⁷  Marta Guevara‐Ferrer⁷  Gennaro Napolitano⁸  Jlenia Monfregola⁸  Sandro Montefusco⁸  Chiara Soldati⁸  Diego L Medina⁸  Andrea Ballabio⁸  Maria A De Matteis⁸  Alessandra Esposito⁸  Luca G Wanderlingh⁸  Stephan Storch⁹ 

[1] Cellular and Chemical Biology Department Institut Curie, U1143 INSERM, UMR3666 CNRS PSL Research University Paris France;Department Osteology & Biomechanics University Medical Center Hamburg‐Eppendorf Hamburg Germany;Faculty of Medicine Walther Straub Institute of Pharmacology and Toxicology Ludwig‐Maximilians University Munich Germany;Institute for Stroke and Dementia Research (ISD) University Hospital LMU Munich Munich Germany;Institute of Functional Biology and Genomics CSIC University of Salamanca Salamanca Spain;Medical Research Council Laboratory for Molecular Cell Biology and UCL Great Ormond Street Institute of Child Health University College London London UK;School of Healthcare Science Manchester Metropolitan University Manchester UK;Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli Naples Italy;University Children's Research@Kinder‐UKE University Medical Center Hamburg‐Eppendorf Hamburg Germany;

关键词: CLN3;    CLN7;    high content imaging screening;    tamoxifen;    TFEB;   

DOI  :  10.15252/emmm.202013742

来源: DOAJ

【 摘 要 】

Abstract Batten diseases (BDs) are a group of lysosomal storage disorders characterized by seizure, visual loss, and cognitive and motor deterioration. We discovered increased levels of globotriaosylceramide (Gb3) in cellular and murine models of CLN3 and CLN7 diseases and used fluorescent‐conjugated bacterial toxins to label Gb3 to develop a cell‐based high content imaging (HCI) screening assay for the repurposing of FDA‐approved compounds able to reduce this accumulation within BD cells. We found that tamoxifen reduced the lysosomal accumulation of Gb3 in CLN3 and CLN7 cell models, including neuronal progenitor cells (NPCs) from CLN7 patient‐derived induced pluripotent stem cells (iPSC). Here, tamoxifen exerts its action through a mechanism that involves activation of the transcription factor EB (TFEB), a master gene of lysosomal function and autophagy. In vivo administration of tamoxifen to the CLN7Δex2 mouse model reduced the accumulation of Gb3 and SCMAS, decreased neuroinflammation, and improved motor coordination. These data strongly suggest that tamoxifen may be a suitable drug to treat some types of Batten disease.

【 授权许可】

Unknown