Transcriptomic Profiling of Medial Temporal Lobe Epilepsy.

Epilepsy is one of the most prevalent neurological disorders affecting ~1% of the population. Medial temporal lobe epilepsy (MTLE) is the most frequent type of epilepsy observed in adults who do not respond to pharmacological treatment. The reason for intractability in these patients has not been systematically studied. Further, no markers are available that can predict the subset of patients who will not respond to pharmacotherapy. To identify potential biomarkers of epileptogenicity, we compared the mRNA profiles of surgically resected tissue from seizure zones with non-seizure zones from cases of intractable MTLE. We identified 413 genes that exhibited ≥2-fold change that were statistically significant across these two groups. Several of these differentially expressed genes have not been previously described in the context of MTLE including claudin 11 (CLDN11) and bone morphogenetic protein receptor, type IB (BMPR1B). In addition, we found significant downregulation of a subset of gamma-aminobutyric acid (GABA) associated genes. We also identified molecules such as BACH2 and ADAMTS15, which are already known to be associated with epilepsy. We validated one upregulated molecule, serine/threonine kinase 31 (STK31) and one downregulated molecule, SMARCA4, by immunohistochemical labeling of tissue sections. These molecules need to be further confirmed in large-scale studies to determine their potential use as diagnostic as well as prognostic markers in intractable MTLE.

[1]  Brahim Tabarki,et al.  Antiepileptic drugs , 2014, Reactions Weekly.

[2]  Munir Pirmohamed,et al.  Exploring the genomic basis of pharmacoresistance in epilepsy: an integrative analysis of large-scale gene expression profiling studies on brain tissue from epilepsy surgery. , 2011, Human molecular genetics.

[3]  M. Szente,et al.  Protein kinase inhibitor as a potential candidate for epilepsy treatment , 2011, Epilepsia.

[4]  T. Schwartz,et al.  Tissue hypoxia correlates with intensity of interictal spikes , 2011, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[5]  Surojit Paul,et al.  NR2B‐NMDA receptor mediated modulation of the tyrosine phosphatase STEP regulates glutamate induced neuronal cell death , 2010, Journal of neurochemistry.

[6]  Wu Ym,et al.  Decreased renal mRNA expression of TRPM6 is associated with hypomagnesemia in C57BL/6 asthmatic mice. , 2010 .

[7]  B. Jeon,et al.  Protein kinase Cdelta is associated with 14-3-3 phosphorylation in seizure-induced neuronal death , 2010, Epilepsy Research.

[8]  A. Giordano,et al.  The BRG1 ATPase of chromatin remodeling complexes is involved in modulation of mesenchymal stem cell senescence through RB–P53 pathways , 2010, Oncogene.

[9]  I. Holopainen,et al.  Transcriptome Analysis of the Hippocampal CA1 Pyramidal Cell Region after Kainic Acid-Induced Status Epilepticus in Juvenile Rats , 2010, PloS one.

[10]  S. Cepok,et al.  The antibody response to oligodendrocyte specific protein in multiple sclerosis , 2010, Journal of Neuroimmunology.

[11]  O. Skalli,et al.  Alpha-actinin 1 and alpha-actinin 4: contrasting roles in the survival, motility, and RhoA signaling of astrocytoma cells. , 2010, Experimental cell research.

[12]  S. Stupp,et al.  BMPR1a and BMPR1b Signaling Exert Opposing Effects on Gliosis after Spinal Cord Injury , 2010, The Journal of Neuroscience.

[13]  Z. Lv,et al.  Decreased renal mRNA expression of TRPM6 is associated with hypomagnesemia in C57BL/6 asthmatic mice. , 2010, European review for medical and pharmacological sciences.

[14]  C. López-Otín,et al.  Genetic inactivation of ADAMTS15 metalloprotease in human colorectal cancer. , 2009, Cancer research.

[15]  T. Neuman,et al.  N‐terminally truncated BAF57 isoforms contribute to the diversity of SWI/SNF complexes in neurons , 2009, Journal of neurochemistry.

[16]  E. Montgomery,et al.  Genomewide mRNA profiling of esophageal squamous cell carcinoma for identification of cancer biomarkers , 2009, Cancer biology & therapy.

[17]  Zhi-Qin Xi,et al.  Altered Expression of Synaptotagmin I In Temporal Lobe Tissue of Patients With Refractory Epilepsy , 2009, Journal of Molecular Neuroscience.

[18]  M. G. Koerkamp,et al.  Possible role of the innate immunity in temporal lobe epilepsy , 2008, Epilepsia.

[19]  Otto W Witte,et al.  Loss of GABAergic neurons in the subiculum and its functional implications in temporal lobe epilepsy. , 2008, Brain : a journal of neurology.

[20]  M. Shamloo,et al.  Expression and function of striatal enriched protein tyrosine phosphatase is profoundly altered in cerebral ischemia , 2008, The European journal of neuroscience.

[21]  S. Yim,et al.  Altered DNA copy number in patients with different seizure disorder type: By array-CGH , 2007, Brain and Development.

[22]  Y. Mishina,et al.  BMPR1a Signaling Determines Numbers of Oligodendrocytes and Calbindin-Expressing Interneurons in the Cortex , 2007, The Journal of Neuroscience.

[23]  E. Aronica,et al.  Gene Expression Profile in Temporal Lobe Epilepsy , 2007, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[24]  J. Naegele,et al.  Status Epilepticus-Induced Somatostatinergic Hilar Interneuron Degeneration Is Regulated by Striatal Enriched Protein Tyrosine Phosphatase , 2007, The Journal of Neuroscience.

[25]  R. Jakus,et al.  Serotonin and epilepsy , 2007, Journal of neurochemistry.

[26]  D. Spencer,et al.  Gene Expression in Temporal Lobe Epilepsy is Consistent with Increased Release of Glutamate by Astrocytes , 2007, Molecular medicine.

[27]  D. Boison.  Adenosine kinase, epilepsy and stroke: mechanisms and therapies. , 2006, Trends in pharmacological sciences.

[28]  G. Lubec,et al.  Bach2 is involved in neuronal differentiation of N1E-115 neuroblastoma cells. , 2006, Experimental cell research.

[29]  J. DeFelipe,et al.  Correlation of transcriptome profile with electrical activity in temporal lobe epilepsy , 2006, Neurobiology of Disease.

[30]  J. Régis,et al.  Large-scale expression study of human mesial temporal lobe epilepsy: evidence for dysregulation of the neurotransmission and complement systems in the entorhinal cortex. , 2006, Brain : a journal of neurology.

[31]  J. Kessler,et al.  Interactions between ID and OLIG proteins mediate the inhibitory effects of BMP4 on oligodendroglial differentiation , 2004, Development.

[32]  W. Wurst,et al.  Reduced Cerebral Injury in CRH-R1 Deficient Mice after Focal Ischemia: A Potential Link to Microglia and Atrocytes that Express CRH-R1 , 2003, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[33]  S. Scherer,et al.  Identification of a novel protein interacting with laforin, the EPM2a progressive myoclonus epilepsy gene product. , 2003, Genomics.

[34]  R. Simon,et al.  Formation of a tumour necrosis factor receptor 1 molecular scaffolding complex and activation of apoptosis signal‐regulating kinase 1 during seizure‐induced neuronal death , 2003, The European journal of neuroscience.

[35]  C. Elger,et al.  Transcriptional profiling in human epilepsy: expression array and single cell real-time qRT-PCR analysis reveal distinct cellular gene regulation , 2002, Neuroreport.

[36]  E. Haddad,et al.  Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family , 2002, Nature Genetics.

[37]  Marcello Massimini,et al.  Spatial Buffering during Slow and Paroxysmal Sleep Oscillations in Cortical Networks of Glial Cells In Vivo , 2002, The Journal of Neuroscience.

[38]  Rafael Yuste,et al.  Calcium oscillations in neocortical astrocytes under epileptiform conditions. , 2002, Journal of neurobiology.

[39]  H. Ichijo,et al.  Negative feedback regulation of ASK1 by protein phosphatase 5 (PP5) in response to oxidative stress , 2001, The EMBO journal.

[40]  J. Bronstein,et al.  Involvement of OSP/claudin‐11 in oligodendrocyte membrane interactions: Role in biology and disease , 2000, Journal of neuroscience research.

[41]  P. Kwan,et al.  Early identification of refractory epilepsy. , 2000, The New England journal of medicine.

[42]  Ingmar Blümcke,et al.  Molecular neuropathology of human mesial temporal lobe epilepsy , 1999, Epilepsy Research.

[43]  C. Polkey,et al.  Glial cell changes in the white matter in temporal lobe epilepsy , 1999, Epilepsy Research.

[44]  U. Ungerstedt,et al.  The secretory trypsin inhibitor like-peptide, PEC-60 increases dopamine D2 receptor agonist induced inhibition of GABA release in the dorsolateral neostriatum of the awake freely moving rat. An in vivo microdialysis study , 1996, Regulatory Peptides.

[45]  M. J. Brodie,et al.  Drug therapy : antiepileptic drugs , 1996 .

[46]  R. Mattson,et al.  Characteristics of medial temporal lobe epilepsy: II. Interictal and ictal scalp electroencephalography, neuropsychological testing, neuroimaging, surgical results, and pathology , 1993, Annals of neurology.

[47]  R. Lightowlers,et al.  Human cytochrome c oxidase subunit VIb: characterization and mapping of a multigene family. , 1991, Gene.

[48]  D. Schmidt.  Two antiepileptic drugs for intractable epilepsy with complex-partial seizures. , 1982, Journal of neurology, neurosurgery, and psychiatry.