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COMMENTARY
Year : 2019  |  Volume : 67  |  Issue : 6  |  Page : 1472--1473

Epigenetic Regulation of mTOR Pathway in Malformations of Cortical Development

Krishan Kumar1, Jyotirmoy Banerjee2, Manjari Tripathi3, P Sarat Chandra4, Aparna B Dixit1,  
1 Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi; Center of Excellence for Epilepsy, AIIMS, New Delhi, India
2 Center of Excellence for Epilepsy; Department of Biophysics, AIIMS, New Delhi, India
3 Center of Excellence for Epilepsy; Department of Neurology, AIIMS, New Delhi, India
4 Center of Excellence for Epilepsy; Department of Neurosurgery, AIIMS, New Delhi, India

Correspondence Address:
Dr. Aparna B Dixit
Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi - 110 007
India




How to cite this article:
Kumar K, Banerjee J, Tripathi M, Chandra P S, Dixit AB. Epigenetic Regulation of mTOR Pathway in Malformations of Cortical Development.Neurol India 2019;67:1472-1473


How to cite this URL:
Kumar K, Banerjee J, Tripathi M, Chandra P S, Dixit AB. Epigenetic Regulation of mTOR Pathway in Malformations of Cortical Development. Neurol India [serial online] 2019 [cited 2023 Jan 28 ];67:1472-1473
Available from: https://www.neurologyindia.com/text.asp?2019/67/6/1472/273613


Full Text



Malformations of cortical development (MCDs) represent a heterogeneous cohort of cortical malformations, including lissencephaly, microcephaly, heterotopia, and focal cortical dysplasia (FCD). MCDs often result in a spectrum of neurological dysfunctions, such as developmental delays, intellectual disability, and refractory epilepsy in pediatric patients. The genetic basis of MCDs is still not fully elucidated, but several somatic and germline mutations have been identified for lissencephaly (LIS1, ARX); microcephaly (MCPH 1, ASPM); tuberous sclerosis complex (TSC1, TSC2); double cortex (DCX); and more recently, for FCD type I (SLC35A2) and FCD type II (PIK3CA, AKT3, TSC1, TSC2, RHEB, MTOR, and DEPDC5).[1],[2] The majority of these genes are linked, directly or indirectly, to AKT/mTOR or REELIN/LIS1 signaling. While over 100 genes have shown to be associated MCDs, there is a dearth of information on epigenetic mechanisms participating in events leading to cortical malformations, epileptogenesis, or both.

In this issue, Sen et al.[3] used microarray-based DNA methylation analysis to investigate differentially methylated genes in MCDs (FCD type I and heterotopia) in comparison with non-MCD controls, where the cause of refractory epilepsy was either inflammation or gliosis.[3] The authors show hypermethylation of genes associated with Reelin signaling (EFNB3, EPHB1); glutathione metabolism (GSTM1, GSTM5, GSTO2); and potassium channels (KCNQ5, KCNG4) in MCD group of patients.

A particularly important finding in this study is the hypermethylation of ephrin B3 in MCDs compared with non-MCD control. Ephrin Bs (EFNB1-3) are important components of the Reelin pathway that regulate neuronal migration through PI3K/AKT and dendritic growth through mTOR signaling.[4],[5] Loss of ephrin Bs was shown to result in neuronal migration defects reminiscent of the Reeler mouse, and the activation of ephrin Bs rescued the migration defects in the absence of Reelin protein. However, the role of ephrins in cortical development has been contested in a recent study, which shows that ephrins do not participate in radial positioning of migrating neocortical pyramidal cells.[6] Increased expression of ephrin B3 is reported in an animal model of temporal lobe epilepsy, as well as in patients.[7] Previous studies have shown the role of ephrin B3 in synaptic stability.[8] It is, therefore, possible that ephrins, while not directly involved in cortical malformation through the canonical signaling pathway, could be a participant in epileptogenic mechanisms. However, Sen et al. provide no correlation between DNA methylation and expression of EFNB3 and EPHB1, making it difficult to interpret the functional relevance of these changes. Further, it is not evident if the methylation changes were present in the promoter regions, intergenic, or gene bodies. Interestingly, a positive correlation between gene body methylation (GBM) and gene expression has also been reported.[9]

Inverse correlation between DNA methylation and gene expression of mTOR pathway-related genes has been reported in FCD II.[10] Dixit et al. showed an inverse correlation between promoter methylation and expression of RPS6KA3 (hypomethylated; upregulated) and PRKAA1(hypermethylated, downregulated) genes using DNA methylation arrays and RNA sequencing. Ribosomal protein S6 kinase A3 (RPSKA3) can activate mTOR signaling either directly through phosphorylation of TSC2 or by phosphorylating RPTOR, which can activate PI3K/AKT-independent mTOR signaling. Similarly, reduced expression of PRKAA1, catalytic subunit of AMPK, could result in a diminution of negative regulation of mTORC1 complex, leading to mTOR pathway activation.

In contrast, no expression changes in mTOR pathway-related genes were reported by Kobow et al. in different types and subtypes of FCD.[11] In this study, differential methylation in the promoter region or gene body of seven mTOR pathway-related genes (FOXO6, GNAQ, PHLPP1, PDPK1, TSC2, DEPDC5, and CNTNAP2) was observed in FCD II compared with nonepileptic controls, but no changes were observed in the expression of these genes. Differential methylation could distinguish different FCD subtypes (Ia, IIa, and IIb), but these changes were not observed in the mTOR pathway-related genes.

Tissue heterogeneity, as suggested by Kobow et al., could be an important compounding factor in these kinds of studies. Neuronal methylation was shown not to be the primary driver of FCD subtype clustering; hence, different proportions of cell types present in a resected brain specimen could lead to different results and interpretations. Comprehensive profiling of neural cell-type-specific methylomes is therefore required for clinicopathologic and molecular assessment of MCDs.

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