Repurposing of tamoxifen ameliorates CLN3 and CLN7 disease phenotype

被引：35

作者：

Soldati, Chiara ^{[1
]}

Lopez-Fabuel, Irene ^{[2
,3
,4
]}

Wanderlingh, Luca G. ^{[1
]}

Garcia-Macia, Marina ^{[2
,3
,4
]}

Monfregola, Jlenia ^{[1
]}

Esposito, Alessandra ^{[1
]}

Napolitano, Gennaro ^{[1
,5
]}

Guevara-Ferrer, Marta ^{[6
]}

Scotto Rosato, Anna ^{[7
]}

Krogsaeter, Einar K. ^{[7
]}

Paquet, Dominik ^{[8
,9
]}

Grimm, Christian M. ^{[7
]}

Montefusco, Sandro ^{[1
]}

Braulke, Thomas ^{[10
]}

Storch, Stephan ^{[11
]}

Mole, Sara E. ^{[12
,13
]}

De Matteis, Maria A. ^{[1
,14
]}

Ballabio, Andrea ^{[1
,5
,15
,16
]}

Sampaio, Julio L. ^{[17
]}

McKay, Tristan ^{[6
]}

Johannes, Ludger ^{[17
]}

Bolanos, Juan P. ^{[2
,3
,4
]}

Medina, Diego L. ^{[1
,5
]}

机构：

[1] Telethon Inst Genet & Med TIGEM, Naples, Italy

[2] Univ Salamanca, CSIC, Inst Funct Biol & Genom, Salamanca, Spain

[3] Inst Salud Carlos III, Ctr Invest Biomed Red Fragilidad & Envejecimiento, Madrid, Spain

[4] Univ Salamanca, CSIC, Univ Hosp Salamanca, Inst Biomed Res Salamanca, Salamanca, Spain

[5] Univ Naples Federico II, Dept Med & Translat Sci, Med Genet Unit, Naples, Italy

[6] Manchester Metropolitan Univ, Sch Healthcare Sci, Manchester, Lancs, England

[7] Ludwig Maximilians Univ Munchen, Walther Straub Inst Pharmacol & Toxicol, Fac Med, Munich, Germany

[8] Ludwig Maximilians Univ Munchen, Univ Hosp, Inst Stroke & Dementia Res ISD, Munich, Germany

[9] Munich Cluster Syst Neurol SyNergy, Munich, Germany

[10] Univ Med Ctr Hamburg Eppendorf, Dept Osteol & Biomech, Hamburg, Germany

[11] Univ Med Ctr Hamburg Eppendorf, Univ Childrens Res Kinder UKE, Hamburg, Germany

[12] UCL, Med Res Council, Lab Mol Cell Biol, London, England

[13] UCL, UCL Great Ormond St Inst Child Hlth, London, England

[14] Univ Napoli Federico II, Dept Mol Med & Med Biotechnol, Naples, Italy

[15] Baylor Coll Med, Houston, TX 77030 USA

[16] Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA

[17] PSL Res Univ, Inst Curie, CNRS, INSERM,Cellular & Chem Biol Dept,UMR3666,U1143, Paris, France

来源：

EMBO MOLECULAR MEDICINE | 2021年 / 13卷 / 10期

基金：

欧盟地平线“2020”; 英国医学研究理事会;

关键词：

CLN3; CLN7; high content imaging screening; tamoxifen; TFEB; NEURONAL CEROID-LIPOFUSCINOSES; MOUSE MODEL; STORAGE; CELLS; MICE; METABOLISM; RALOXIFENE; RESISTANCE; MORPHOLOGY; AUTOPHAGY;

D O I：

10.15252/emmm.202013742

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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 CLN7(Delta ex2) 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.

引用

页数：19

共 62 条

[1] Reduction of globotriaosylceramide in Fabry disease mice by substrate deprivation [J].