کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
6022147 | 1580664 | 2013 | 11 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Levetiracetam resistance: Synaptic signatures & corresponding promoter SNPs in epileptic hippocampi
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
علم عصب شناسی
عصب شناسی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Here, we followed a different approach to study the mechanisms of LEV pharmacoresistance by screening for mRNA signatures specifically expressed in LEV a priori non-responders in epileptic brain tissue and subsequent promoter analyses of highly altered transcripts. To this end, we have used our unique access to analyze hippocampal tissue from pharmacoresistant TLE patients who underwent epilepsy surgery for seizure control (n = 53) stratified according to a priori LEV responders versus patients with impaired LEV-response. Transcriptome (Illumina platform) and subsequent multimodal cluster analyses uncovered strikingly abundant synapse-associated molecule mRNA signatures in LEV a priori non-responders. Subsequent promoter characterization revealed accumulation of the single nucleotide polymorphism (SNP) rs9305614 G-allele in a priori non-responders to correlate to abundant mRNAs of phosphatidylinositol N-acetylglucosaminyltransferase (PIGP), i.e. a key component of the Wnt-signaling pathway. By luciferase assays, we observed significantly stronger activation by the LBP-1 transcription factor of the rs9305614 G-allele PIGP promoter. The present data suggest an abundance of transcripts encoding for key synaptic components in the hippocampi of LEV a priori non-responder mTLE patients, which for PIGP as proof of concept can be explained by a particular promoter variant. Our data argue for epigenetic factors predisposing for a priori LEV pharmacoresistance by transcriptional 'overexposure of targets'.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neurobiology of Disease - Volume 60, December 2013, Pages 115-125
Journal: Neurobiology of Disease - Volume 60, December 2013, Pages 115-125
نویسندگان
Tanja Grimminger, Katharina Pernhorst, Rainer Surges, Pitt Niehusmann, Lutz Priebe, Marec von Lehe, Per Hoffmann, Sven Cichon, Susanne Schoch, Albert J. Becker,