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Acta Neuropathologica
Published in: Acta Neuropathologica 2/2013

01-08-2013 | Original Paper

mTOR-dependent abnormalities in autophagy characterize human malformations of cortical development: evidence from focal cortical dysplasia and tuberous sclerosis

Authors: Shireena A. Yasin, Abu M. Ali, Mathew Tata, Simon R. Picker, Glenn W. Anderson, Elizabeth Latimer-Bowman, Sarah L. Nicholson, William Harkness, J. Helen Cross, Simon M. L. Paine, Thomas S. Jacques

Published in: Acta Neuropathologica | Issue 2/2013

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Abstract

Focal cortical dysplasia (FCD) is a localized malformation of cortical development and is the commonest cause of severe childhood epilepsy in surgical practice. Children with FCD are severely disabled by their epilepsy, presenting with frequent seizures early in life. The commonest form of FCD in children is characterized by the presence of an abnormal population of cells, known as balloon cells. Similar pathological changes are seen in the cortical malformations that characterize patients with tuberous sclerosis complex (TSC). However, the cellular and molecular mechanisms that underlie the malformations of FCD and TSC are not well understood. We provide evidence for a defect in autophagy in FCD and TSC. We have found that balloon cells contain vacuoles that include components of the autophagy pathway. Specifically, we show that balloon cells contain prominent lysosomes by electron microscopy, immunohistochemistry for LAMP1 and LAMP2, LysoTracker labelling and enzyme histochemistry for acid phosphatase. Furthermore, we found that balloon cells contain components of the ATG pathway and that there is cytoplasmic accumulation of the regulator of autophagy, DOR. Most importantly we found that there is abnormal accumulation of the autophagy cargo protein, p62. We show that this defect in autophagy can be, in part, reversed in vitro by inhibition of the mammalian target of rapamycin (mTOR) suggesting that abnormal activation of mTOR may contribute directly to a defect in autophagy in FCD and TSC.
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Metadata
Title
mTOR-dependent abnormalities in autophagy characterize human malformations of cortical development: evidence from focal cortical dysplasia and tuberous sclerosis
Authors
Shireena A. Yasin
Abu M. Ali
Mathew Tata
Simon R. Picker
Glenn W. Anderson
Elizabeth Latimer-Bowman
Sarah L. Nicholson
William Harkness
J. Helen Cross
Simon M. L. Paine
Thomas S. Jacques
Publication date
01-08-2013
Publisher
Springer Berlin Heidelberg
Published in
Acta Neuropathologica / Issue 2/2013
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-013-1135-4

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