title: Reduced mature microRNA levels in association with dicer loss in human temporal lobe epilepsy with hippocampal sclerosis.
abstract: Hippocampal sclerosis (HS) is a common pathological finding in patients with temporal lobe epilepsy (TLE) and is associated with altered expression of genes controlling neuronal excitability, glial function, neuroinflammation and cell death. MicroRNAs (miRNAs), a class of small non-coding RNAs, function as post-transcriptional regulators of gene expression and are critical for normal brain development and function. Production of mature miRNAs requires Dicer, an RNAase III, loss of which has been shown to cause neuronal and glial dysfunction, seizures, and neurodegeneration. Here we investigated miRNA biogenesis in hippocampal and neocortical resection specimens from pharmacoresistant TLE patients and autopsy controls. Western blot analysis revealed protein levels of Dicer were significantly lower in certain TLE patients with HS. Dicer levels were also reduced in the hippocampus of mice subject to experimentally-induced epilepsy. To determine if Dicer loss was associated with altered miRNA processing, we profiled levels of 380 mature miRNAs in control and TLE-HS samples. Expression of nearly 200 miRNAs was detected in control human hippocampus. In TLE-HS samples there was a large-scale reduction of miRNA expression, with 51% expressed at lower levels and a further 24% not detectable. Primary transcript (pri-miRNAs) expression levels for several tested miRNAs were not different between control and TLE-HS samples. These findings suggest loss of Dicer and failure of mature miRNA expression may be a feature of the pathophysiology of HS in patients with TLE.
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Ross C
authors.initials: RC
authors.lastname: McKiernan
authors.forename: Eva M
authors.initials: EM
authors.lastname: Jimenez-Mateos
authors.forename: Isabella
authors.initials: I
authors.lastname: Bray
authors.forename: Tobias
authors.initials: T
authors.lastname: Engel
authors.forename: Gary P
authors.initials: GP
authors.lastname: Brennan
authors.forename: Takanori
authors.initials: T
authors.lastname: Sano
authors.forename: Zuzanna
authors.initials: Z
authors.lastname: Michalak
authors.forename: Catherine
authors.initials: C
authors.lastname: Moran
authors.forename: Norman
authors.initials: N
authors.lastname: Delanty
authors.forename: Michael
authors.initials: M
authors.lastname: Farrell
authors.forename: Donncha
authors.initials: D
authors.lastname: O'Brien
authors.forename: Robert
authors.initials: R
authors.lastname: Meller
authors.forename: Roger P
authors.initials: RP
authors.lastname: Simon
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Stallings
authors.forename: David C
authors.initials: DC
authors.lastname: Henshall
mesh_terms: D000328:Adult; D000818:Animals; D019295:Computational Biology; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D004833:Epilepsy, Temporal Lobe / Q000235:genetics*; D005260:Female; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D043244:Ribonuclease III / Q000235:genetics*; D012598:Sclerosis / Q000235:genetics*
chemical_list: D035683:MicroRNAs; C408087:DICER1 protein, human; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases