title: Neuropathological signs of inflammation correlate with mitochondrial DNA deletions in mesial temporal lobe epilepsy.
abstract: Accumulation of mitochondrial DNA (mtDNA) deletions has been proposed to be responsible for the presence of respiratory-deficient neurons in several CNS diseases. Deletions are thought to originate from double-strand breaks due to attack of reactive oxygen species (ROS) of putative inflammatory origin. In epileptogenesis, emerging evidence points to chronic inflammation as an important feature. Here we aimed to analyze the potential association of inflammation and mtDNA deletions in the hippocampal tissue of patients with mesial temporal lobe epilepsy (mTLE) and hippocampal sclerosis (HS). Hippocampal and parahippocampal tissue samples from 74 patients with drug-refractory mTLE served for mtDNA analysis by multiplex PCR as well as long-range PCR, single-molecule PCR and ultra-deep sequencing of mtDNA in selected samples. Patients were sub-classified according to neuropathological findings. Semi-quantitative assessment of neuronal cell loss was performed in the hippocampal regions CA1-CA4. Inflammatory infiltrates were quantified by cell counts in the CA1, CA3 and CA4 regions from well preserved hippocampal samples (n = 33). Samples with HS showed a significantly increased frequency of a 7436-bp mtDNA deletion (p < 0.0001) and a higher proportion of somatic G>T transversions compared to mTLE patients with different histopathology. Interestingly, the number of T-lymphocytes in the hippocampal CA1, CA3 and CA4 regions was, similar to the 7436-bp mtDNA deletion, significantly increased in samples with HS compared to other subgroups. Our findings show a coincidence of HS, increased somatic G>T transversions, the presence of a specific mtDNA deletion, and increased inflammatory infiltrates. These results support the hypothesis that chronic inflammation leads to mitochondrial dysfunction by ROS-mediated mtDNA mutagenesis which promotes epileptogenesis and neuronal cell loss in patients with mTLE and HS.
authors.affiliation: Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Elisa
authors.initials: E
authors.lastname: Volmering
authors.affiliation: Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.|Department of Neuro-/Pathology, Oslo University Hospital, Oslo, Norway.
authors.forename: Pitt
authors.initials: P
authors.lastname: Niehusmann
authors.affiliation: Division of Neurochemistry, Department of Epileptology, University Bonn Medical Center, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.
authors.forename: Viktoriya
authors.initials: V
authors.lastname: Peeva
authors.affiliation: Department of Neurosurgery, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Grote
authors.affiliation: Division of Neurochemistry, Department of Epileptology, University Bonn Medical Center, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.
authors.forename: Gábor
authors.initials: G
authors.lastname: Zsurka
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.|Institute of Human Genetics, University of Cologne, Cologne, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.|Translational Epilepsy Research Section, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Becker
authors.affiliation: Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.|Translational Epilepsy Research Section, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schoch
authors.affiliation: Division of Neurochemistry, Department of Epileptology, University Bonn Medical Center, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.
authors.forename: Christian E
authors.initials: CE
authors.lastname: Elger
authors.affiliation: Division of Neurochemistry, Department of Epileptology, University Bonn Medical Center, Sigmund-Freud-Str. 25, 53105, Bonn, Germany. wolfram.kunz@ukb.uni-bonn.de.
authors.forename: Wolfram S
authors.identifier: http://orcid.org/0000-0003-1113-3493
authors.initials: WS
authors.lastname: Kunz
mesh_terms: D000328:Adult; D004272:DNA, Mitochondrial / Q000235:genetics*; D004833:Epilepsy, Temporal Lobe / Q000235:genetics / Q000378:metabolism*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000473:pathology*; D012598:Sclerosis / Q000473:pathology*
chemical_list: D004272:DNA, Mitochondrial
keywords: Hippocampal sclerosis neuropathology; Inflammation; Mitochondria; Temporal lobe epilepsy; mtDNA deletions