Acta Neuropathologica

, Volume 126, Issue 2, pp 207–218

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

  • 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
Original Paper

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.

Keywords

Autophagy Epilepsy Balloon cells Focal cortical dysplasia Tuberous sclerosis 

Supplementary material

Supplementary video 1 LysoTracker™ labelling of cultured balloon cells showed that they contained abundant lysosomes, which were dynamic in culture. Lysosomes were particularly concentrated close to the nucleus and were dynamic in the periphery of cells (MP4 152 kb)

401_2013_1135_MOESM2_ESM.tiff (650 kb)
Supplementary figure 2 Balloon cells show down-regulation of pS6 and p62 in response to rapamycin (a–f). Immunofluorescence for pS6 (a and d) and p62 (b and e) in control media (upper row) and rapamycin (lower row, 500 nM) (Scale bar = 30 μm). Balloon cells are indicated by arrows in the rapamycin condition (TIFF 650 kb)
401_2013_1135_MOESM3_ESM.doc (27 kb)
Supplementary table 3 The table summarizes the clinical features of the cohort of patients used in the study (DOC 27 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Shireena A. Yasin
    • 1
    • 3
  • Abu M. Ali
    • 1
  • Mathew Tata
    • 1
  • Simon R. Picker
    • 1
    • 3
    • 6
  • Glenn W. Anderson
    • 3
  • Elizabeth Latimer-Bowman
    • 3
  • Sarah L. Nicholson
    • 3
  • William Harkness
    • 2
    • 4
  • J. Helen Cross
    • 2
    • 5
  • Simon M. L. Paine
    • 1
    • 3
  • Thomas S. Jacques
    • 1
    • 3
  1. 1.Neural Development Unit, Birth Defects Research CentreUCL Institute of Child HealthLondonUK
  2. 2.Neurosciences UnitUCL Institute of Child HealthLondonUK
  3. 3.Department of HistopathologyGreat Ormond Street Hospital for Children NHS Foundation TrustLondonUK
  4. 4.Department of NeurosurgeryGreat Ormond Street Hospital for Children NHS Foundation TrustLondonUK
  5. 5.Department of NeurologyGreat Ormond Street Hospital for Children NHS Foundation TrustLondonUK
  6. 6.MRC National Institute for Medical ResearchLondonUK

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