title: Gene expression variance in hippocampal tissue of temporal lobe epilepsy patients corresponds to differential memory performance.
abstract: Temporal lobe epilepsy (TLE) is a severe brain disorder affecting particularly young adults. TLE is frequently associated with memory deterioration and neuronal damage of the hippocampal formation. It thereby reveals striking parallels to neurodegenerative disorders including Alzheimer's disease (AD). TLE patients differ with respect to their cognitive performance, but currently little is known about relevant molecular-genetic factors. Here, we correlated differential memory performance of pharmacoresistant TLE patients undergoing neurosurgery for seizure control with in-vitro findings of their hippocampal tissues. We analyzed mRNA transcripts and subsequently promoter variants specifically altered in brain tissue of individuals with 'very severe' memory impairment. TLE patients (n=79) were stratified according to preoperative memory impairment using an established four-tiered grading system ranging from 'average' to 'very severely'. Multimodal cluster analyses revealed molecules specifically associated with synaptic function and abundantly expressed in TLE patients with very impaired memory performance. In a subsequent promoter analysis, we found the single nucleotide polymorphism rs744373 C-allele to be associated with high mRNA levels of bridging integrator 1 (BIN1)/Amphiphysin 2, i.e. a major component of the endocytotic machinery and located in a crucial genetic AD risk locus. Using in vitro luciferase transfection assays, we found that BIN1 promoter activation is genotype dependent and strongly increased by reduced binding of the transcriptional repressor TGIF. Our data indicate that poor memory performance in patients with TLE strongly corresponds to distinctly altered neuronal transcript signatures, which - as demonstrated for BIN1 - can correlate with a particular allelic promoter variant. Our data suggest aberrant transcriptional signaling to significantly impact synaptic dynamics in TLE resulting in impaired memory performance and may serve as basis for future therapy development of this severe comorbidity.
authors.affiliation: Dept. of Neuropathology, University of Bonn Medical Center, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Bungenberg
authors.affiliation: Dept. of Neuropathology, University of Bonn Medical Center, Germany.
authors.forename: Natascha
authors.initials: N
authors.lastname: Surano
authors.affiliation: Dept. of Neurosurgery, University of Bonn Medical Center, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Grote
authors.affiliation: Dept. of Epileptology, University of Bonn Medical Center, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Surges
authors.affiliation: Dept. of Neuropathology, University of Bonn Medical Center, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Pernhorst
authors.affiliation: Institute of Human Genetics, Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hofmann
authors.affiliation: Dept. of Neuropathology, University of Bonn Medical Center, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schoch
authors.affiliation: Dept. of Epileptology, University of Bonn Medical Center, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Helmstaedter
authors.affiliation: Dept. of Neuropathology, University of Bonn Medical Center, Germany. Electronic address: albert_becker@uni-bonn.de.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Becker
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004833:Epilepsy, Temporal Lobe / Q000150:complications / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006624:Hippocampus / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008568:Memory / Q000502:physiology; D008569:Memory Disorders / Q000209:etiology / Q000235:genetics*; D008875:Middle Aged; D009483:Neuropsychological Tests; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics; D012720:Severity of Illness Index; D025521:Tumor Suppressor Proteins / Q000235:genetics; D014706:Verbal Learning / Q000502:physiology; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C101410:BIN1 protein, human; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C097504:TGIF1 protein, human; D025521:Tumor Suppressor Proteins
keywords: BIN1; Figural memory performance; Luciferase; Promoter variants