Knockdown of MLC1 in primary astrocytes causes cell vacuolation: a MLC disease cell model

Duarri, Anna, Lopez de Heredia, Miguel, Capdevila-Nortes, Xavier, Ridder, Margreet C., Montolio, Marisol, López-Hernández, Tania, Boor, Ilja, Lien, Chun-Fu, Hagemann, Tracy, Messing, Albee, Gorecki, Dariusz C., Scheper, Gert C., Martínez, Albert, Nunes, Virginia, van der Knaap, Marjo S. and Estévez, Raúl (2011) Knockdown of MLC1 in primary astrocytes causes cell vacuolation: a MLC disease cell model. Neurobiology of Disease, 43 1: 228-238. doi:10.1016/j.nbd.2011.03.015

Author Duarri, Anna
Lopez de Heredia, Miguel
Capdevila-Nortes, Xavier
Ridder, Margreet C.
Montolio, Marisol
López-Hernández, Tania
Boor, Ilja
Lien, Chun-Fu
Hagemann, Tracy
Messing, Albee
Gorecki, Dariusz C.
Scheper, Gert C.
Martínez, Albert
Nunes, Virginia
van der Knaap, Marjo S.
Estévez, Raúl
Title Knockdown of MLC1 in primary astrocytes causes cell vacuolation: a MLC disease cell model
Journal name Neurobiology of Disease   Check publisher's open access policy
ISSN 0969-9961
Publication date 2011
Sub-type Article (original research)
DOI 10.1016/j.nbd.2011.03.015
Open Access Status
Volume 43
Issue 1
Start page 228
End page 238
Total pages 11
Place of publication Maryland Heights, MO, United States
Publisher Academic Press
Language eng
Abstract Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of leukodystrophy, in the majority of cases caused by mutations in the MLC1 gene. MRI from MLC patients shows diffuse cerebral white matter signal abnormality and swelling, with evidence of increased water content. Histopathology in a MLC patient shows vacuolation of myelin, which causes the cerebral white matter swelling. MLC1 protein is expressed in astrocytic processes that are part of blood- and cerebrospinal fluid-brain barriers. We aimed to create an astrocyte cell model of MLC disease. The characterization of rat astrocyte cultures revealed MLC1 localization in cell-cell contacts, which contains other proteins described typically in tight and adherent junctions. MLC1 localization in these contacts was demonstrated to depend on the actin cytoskeleton; it was not altered when disrupting the microtubule or the GFAP networks. In human tissues, MLC1 and the protein Zonula Occludens 1 (ZO-1), which is linked to the actin cytoskeleton, co-localized by EM immunostaining and were specifically co-immunoprecipitated. To create an MLC cell model, knockdown of MLC1 in primary astrocytes was performed. Reduction of MLC1 expression resulted in the appearance of intracellular vacuoles. This vacuolation was reversed by the co-expression of human MLC1. Re-examination of a human brain biopsy from an MLC patient revealed that vacuoles were also consistently present in astrocytic processes. Thus, vacuolation of astrocytes is also a hallmark of MLC disease.
Keyword Astrocyte
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 23 times in Thomson Reuters Web of Science Article | Citations
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Created: Mon, 27 Oct 2014, 15:52:36 EST by Debra McMurtrie on behalf of Queensland Brain Institute