Journal article
Modulating membrane fluidity corrects Batten disease phenotypes in vitro and in vivo
Neurobiology of disease, Vol.115, pp.182-193
07/01/2018
DOI: 10.1016/j.nbd.2018.04.010
PMCID: PMC5969532
PMID: 29660499
Abstract
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.
Details
- Title: Subtitle
- Modulating membrane fluidity corrects Batten disease phenotypes in vitro and in vivo
- Creators
- Mark L. Schultz - Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USALuis Tecedor - Children's Hospital of PhiladelphiaElena Lysenko - Children's Hospital of PhiladelphiaShyam Ramachandran - Children's Hospital of PhiladelphiaColleen S. Stein - University of IowaBeverly L. Davidson - Children's Hospital of Philadelphia
- Resource Type
- Journal article
- Publication Details
- Neurobiology of disease, Vol.115, pp.182-193
- DOI
- 10.1016/j.nbd.2018.04.010
- PMID
- 29660499
- PMCID
- PMC5969532
- NLM abbreviation
- Neurobiol Dis
- ISSN
- 0969-9961
- eISSN
- 1095-953X
- Publisher
- Elsevier
- Number of pages
- 12
- Grant note
- Beyond Batten Disease Foundation Fellowship Roy J. Carver Trust IIA-1301765 / NSF; National Science Foundation (NSF) Children's Hospital of Philadelphia Research Institute P20GM103446 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) 1S10RR025439-01 / UI Central Microscopy and Research Facility State of Delaware P20 GM103446 / NIH-NIGMs; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) S10RR025439 / NATIONAL CENTER FOR RESEARCH RESOURCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) BDSRA Fellowship
- Language
- English
- Date published
- 07/01/2018
- Academic Unit
- Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Internal Medicine
- Record Identifier
- 9984366292702771
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