Modulating membrane fluidity corrects Batten disease phenotypes in vitro and in vivo

NEUROBIOLOGY OF DISEASE

卷:115

Article

Schultz, Mark L.¹  Tecedor, Luis²  Lysenko, Elena²  Ramachandran, Shyam²  Stein, Colleen S.¹  Davidson, Beverly L.^2,3 

[1] Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA

[2] Childrens Hosp Philadelphia, Raymond G Perelman Ctr Cellular & Mol Therapeut, Philadelphia, PA 19104 USA

[3] Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

关键词: Neuronal ceroid lipofuscinoses;    JNCL;    CLN3;    Cav-1;    Cdc42;    Blood-brain barrier;    Carbenoxolone;    Membrane fluidity;   

DOI  :  10.1016/j.nbd.2018.04.010

来源: Elsevier

【 摘 要 】

The neuronal ceroid lipofuscinoses are a class of inherited neurodegenerative diseases characterized by the accumulation of autofluorescent storage material. The most common neuronal ceroid lipofuscinosis has juvenile onset with rapid onset blindness and progressive degeneration of cognitive processes. The juvenile form is caused by mutations in the CLN3 gene, which encodes the protein CLN3. While mouse models of Cln3 deficiency show mild disease phenotypes, it is apparent from patient tissue- and cell-based studies that its loss impacts many cellular processes. Using Cln3 deficient mice, we previously described defects in mouse brain endothelial cells and blood-brain barrier (BBB) permeability. Here we expand on this to other components of the BBB and show that Cln3 deficient mice have increased astrocyte endfeet area. Interestingly, this phenotype is corrected by treatment with a commonly used GAP junction inhibitor, carbenoxolone (CBX). In addition to its action on GAP junctions, CBX has also been proposed to alter lipid microdomains. In this work, we show that CBX modifies lipid microdomains and corrects membrane fluidity alterations in Cln3 deficient endothelial cells, which in turn improves defects in endocytosis, caveolin-1 distribution at the plasma membrane, and Cdc42 activity. In further work using the NIH Library of Integrated Network-based Cellular Signatures (LINCS), we discovered other small molecules whose impact was similar to CBX in that they improved Cln3-deficient cell phenotypes. Moreover, Cln3 deficient mice treated orally with CBX exhibited recovery of impaired BBB responses and reduced auto fluorescence. CBX and the compounds identified by LINCS, many of which have been used in humans or approved for other indications, may find therapeutic benefit in children suffering from CLN3 deficiency through mechanisms independent of their original intended use.

【 授权许可】

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