PMID- 23728790
OWN - NLM
STAT- MEDLINE
DCOM- 20131022
LR  - 20231213
IS  - 1432-0533 (Electronic)
IS  - 0001-6322 (Linking)
VI  - 126
IP  - 2
DP  - 2013 Aug
TI  - mTOR-dependent abnormalities in autophagy characterize human malformations of 
      cortical development: evidence from focal cortical dysplasia and tuberous 
      sclerosis.
PG  - 207-18
LID - 10.1007/s00401-013-1135-4 [doi]
AB  - 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.
FAU - Yasin, Shireena A
AU  - Yasin SA
AD  - Neural Development Unit, Birth Defects Research Centre, UCL Institute of Child 
      Health, 30 Guilford Street, London, WC1N 1EH, UK.
FAU - Ali, Abu M
AU  - Ali AM
FAU - Tata, Mathew
AU  - Tata M
FAU - Picker, Simon R
AU  - Picker SR
FAU - Anderson, Glenn W
AU  - Anderson GW
FAU - Latimer-Bowman, Elizabeth
AU  - Latimer-Bowman E
FAU - Nicholson, Sarah L
AU  - Nicholson SL
FAU - Harkness, William
AU  - Harkness W
FAU - Cross, J Helen
AU  - Cross JH
FAU - Paine, Simon M L
AU  - Paine SM
FAU - Jacques, Thomas S
AU  - Jacques TS
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130602
PL  - Germany
TA  - Acta Neuropathol
JT  - Acta neuropathologica
JID - 0412041
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (LAMP1 protein, human)
RN  - 0 (LAMP2 protein, human)
RN  - 0 (Lysosomal-Associated Membrane Protein 2)
RN  - 0 (Lysosomal Membrane Proteins)
RN  - 0 (SQSTM1 protein, human)
RN  - 0 (Sequestosome-1 Protein)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.3.2 (Acid Phosphatase)
RN  - Focal cortical dysplasia of Taylor
SB  - IM
MH  - Acid Phosphatase/metabolism
MH  - Adaptor Proteins, Signal Transducing/metabolism
MH  - Autophagy/*physiology
MH  - Brain/abnormalities/metabolism/pathology
MH  - Brain Diseases/metabolism/*pathology
MH  - Cells, Cultured
MH  - Child
MH  - Cytoplasm/metabolism/pathology
MH  - Epilepsy
MH  - Humans
MH  - Immunohistochemistry
MH  - Lysosomal-Associated Membrane Protein 2
MH  - Lysosomal Membrane Proteins/metabolism
MH  - Lysosomes/*pathology/ultrastructure
MH  - Malformations of Cortical Development/metabolism/*pathology
MH  - Malformations of Cortical Development, Group I
MH  - Sequestosome-1 Protein
MH  - TOR Serine-Threonine Kinases/metabolism/*physiology
MH  - Tissue Banks
MH  - Tuberous Sclerosis/metabolism/*pathology
EDAT- 2013/06/04 06:00
MHDA- 2013/10/23 06:00
CRDT- 2013/06/04 06:00
PHST- 2013/02/14 00:00 [received]
PHST- 2013/05/24 00:00 [accepted]
PHST- 2013/05/23 00:00 [revised]
PHST- 2013/06/04 06:00 [entrez]
PHST- 2013/06/04 06:00 [pubmed]
PHST- 2013/10/23 06:00 [medline]
AID - 10.1007/s00401-013-1135-4 [doi]
PST - ppublish
SO  - Acta Neuropathol. 2013 Aug;126(2):207-18. doi: 10.1007/s00401-013-1135-4. Epub 
      2013 Jun 2.