Dataset Information

MicroRNA-34a activation in tuberous sclerosis complex during early brain development may lead to impaired corticogenesis.

ABSTRACT:

Aims

Tuberous sclerosis complex (TSC) is a genetic disorder associated with dysregulation of the mechanistic target of rapamycin complex 1 (mTORC1) signalling pathway. Neurodevelopmental disorders, frequently present in TSC, are linked to cortical tubers in the brain. We previously reported microRNA-34a (miR-34a) among the most upregulated miRs in tubers. Here, we characterised miR-34a expression in tubers with the focus on the early brain development and assessed the regulation of mTORC1 pathway and corticogenesis by miR-34a.

Methods

We analysed the expression of miR-34a in resected cortical tubers (n = 37) compared with autopsy-derived control tissue (n = 27). The effect of miR-34a overexpression on corticogenesis was assessed in mice at E18. The regulation of the mTORC1 pathway and the expression of the bioinformatically predicted target genes were assessed in primary astrocyte cultures from three patients with TSC and in SH-SY5Y cells following miR-34a transfection.

Results

The peak of miR-34a overexpression in tubers was observed during infancy, concomitant with the presence of pathological markers, particularly in giant cells and dysmorphic neurons. miR-34a was also strongly expressed in foetal TSC cortex. Overexpression of miR-34a in mouse embryos decreased the percentage of cells migrated to the cortical plate. The transfection of miR-34a mimic in TSC astrocytes negatively regulated mTORC1 and decreased the expression of the target genes RAS related (RRAS) and NOTCH1.

Conclusions

MicroRNA-34a is most highly overexpressed in tubers during foetal and early postnatal brain development. miR-34a can negatively regulate mTORC1; however, it may also contribute to abnormal corticogenesis in TSC.

SUBMITTER: Korotkov A

PROVIDER: S-EPMC8519131 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Publications

MicroRNA-34a activation in tuberous sclerosis complex during early brain development may lead to impaired corticogenesis.

Korotkov Anatoly A Sim Nam Suk NS Luinenburg Mark J MJ Anink Jasper J JJ van Scheppingen Jackelien J Zimmer Till S TS Bongaarts Anika A Broekaart Diede W M DWM Mijnsbergen Caroline C Jansen Floor E FE Van Hecke Wim W Spliet Wim G M WGM van Rijen Peter C PC Feucht Martha M Hainfellner Johannes A JA Kršek Pavel P Zamecnik Josef J Crino Peter B PB Kotulska Katarzyna K Lagae Lieven L Jansen Anna C AC Kwiatkowski David J DJ Jozwiak Sergiusz S Curatolo Paolo P Mühlebner Angelika A Lee Jeong H JH Mills James D JD van Vliet Erwin A EA Aronica Eleonora E

Neuropathology and applied neurobiology 20210614 6

<h4>Aims</h4>Tuberous sclerosis complex (TSC) is a genetic disorder associated with dysregulation of the mechanistic target of rapamycin complex 1 (mTORC1) signalling pathway. Neurodevelopmental disorders, frequently present in TSC, are linked to cortical tubers in the brain. We previously reported microRNA-34a (miR-34a) among the most upregulated miRs in tubers. Here, we characterised miR-34a expression in tubers with the focus on the early brain development and assessed the regulation of mTORC ...[more]

PMID: 33942341

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Project description:ObjectiveTo estimate health-related quality of life (HRQoL) in patients with tuberous sclerosis complex (TSC) and associated manifestations and to identify potential factors associated with HRQoL in this population of patients.MethodsWe performed a retrospective chart review of adults with TSC who attended the outpatient clinic of the University Medical Center Utrecht in the Netherlands from 1990 to 2015 (N = 363; on average 33.6 years of follow-up). HRQoL data were assessed in 2012 using the Health Utility Index version 3 (HUI-3) questionnaire completed by patients or caregivers (N = 214 with HUI score and ≥1 TSC manifestation, including renal angiomyolipomas [rAMLs], subependymal giant cell astrocytoma [SEGA], or epilepsy).ResultsOf 214 patients in the study sample, 171 had TSC-associated epilepsy (with or without rAML/SEGA), 37 had TSC and rAML (without epilepsy or SEGA), and 6 had other combinations of manifestations. The median HUI score for the 214 patients with ≥1 TSC manifestation was 0.51 (-0.371 to 1 scale, 1 = perfect health, 0 = death, <0 = worse than death). Among all components used to build the overall HUI score, the cognition component had the lowest score (mean = 0.47; 0-1 scale). Patients with TSC-epilepsy had significantly lower overall HUI than patients with TSC and rAML only (median HUI = 0.31 vs 0.95, P < .05), especially those who were in refractory state for prolonged periods of time (median HUI = -0.11 among patients with seizures during the entire duration of their follow-up time). In multivariate analyses, severe impairment of daily functioning was the strongest predictor of HRQoL decrement (adjusted HUI difference between patients with severe vs. no impairment = -0.55, P < .05).SignificanceThis study showed that TSC-related epilepsy is associated with lower HUI, especially for patients who have refractory seizures for prolonged periods of time. Early and effective interventions to control or reduce seizures and preserve patients' cognitive functions may help to improve patients' quality of life.

Dataset Information

MicroRNA-34a activation in tuberous sclerosis complex during early brain development may lead to impaired corticogenesis.

Aims

Methods

Results

Conclusions

Publications

MicroRNA-34a activation in tuberous sclerosis complex during early brain development may lead to impaired corticogenesis.

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