Format

Send to

Choose Destination
Sci Rep. 2017 Aug 14;7(1):8089. doi: 10.1038/s41598-017-06145-8.

Coding and small non-coding transcriptional landscape of tuberous sclerosis complex cortical tubers: implications for pathophysiology and treatment.

Author information

1
Department of (Neuro) Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
2
GenomeScan BV, Leiden, The Netherlands.
3
Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
4
Department of Neurosurgery, Rudolf Magnus Institute for Neuroscience, University Medical Center, Utrecht, The Netherlands.
5
Department of Pediatric Neurology, Rudolf Magnus Institute for Neuroscience, University Medical Center, Utrecht, The Netherlands.
6
Department of Pediatrics, Medical University Vienna, Vienna, Austria.
7
Institute of Neurology, Medical University Vienna, Vienna, Austria.
8
Department of Pediatric Neurology, 2nd Faculty of Medicine and Motol University Hospital, Prague, Czech Republic.
9
Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine and Motol University Hospital, Prague, Czech Republic.
10
Department of Neurology and Epileptology, The Children's Memorial Health Institute, and Department of Child Neurology, Warsaw Medical University, Warsaw, Poland.
11
Pediatric Neurology Unit - UZ Brussel, Brussels, Belgium.
12
Department of Development and Regeneration-Section Pediatric Neurology, University Hospitals KU Leuven, Leuven, Belgium.
13
Systems Medicine Department, Child Neurology and Psychiatry Unit, Tor Vergata University Hospital of Rome, Rome, Italy.
14
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
15
Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
16
Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands.
17
Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.
18
Center for Experimental & Molecular Medicine, and Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center University of Amsterdam, Amsterdam, The Netherlands.
19
Department of (Neuro) Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. e.aronica@amc.uva.nl.
20
Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands. e.aronica@amc.uva.nl.
21
Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, The Netherlands. e.aronica@amc.uva.nl.

Abstract

Tuberous Sclerosis Complex (TSC) is a rare genetic disorder that results from a mutation in the TSC1 or TSC2 genes leading to constitutive activation of the mechanistic target of rapamycin complex 1 (mTORC1). TSC is associated with autism, intellectual disability and severe epilepsy. Cortical tubers are believed to represent the neuropathological substrates of these disabling manifestations in TSC. In the presented study we used high-throughput RNA sequencing in combination with systems-based computational approaches to investigate the complexity of the TSC molecular network. Overall we detected 438 differentially expressed genes and 991 differentially expressed small non-coding RNAs in cortical tubers compared to autopsy control brain tissue. We observed increased expression of genes associated with inflammatory, innate and adaptive immune responses. In contrast, we observed a down-regulation of genes associated with neurogenesis and glutamate receptor signaling. MicroRNAs represented the largest class of over-expressed small non-coding RNA species in tubers. In particular, our analysis revealed that the miR-34 family (including miR-34a, miR-34b and miR-34c) was significantly over-expressed. Functional studies demonstrated the ability of miR-34b to modulate neurite outgrowth in mouse primary hippocampal neuronal cultures. This study provides new insights into the TSC transcriptomic network along with the identification of potential new treatment targets.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center