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.

Center for Experimental and Molecular Medicine and Department of Clinical Epidemiology Biostatistics and Bioinformatics Academic Medical Center University of Amsterdam Amsterdam The Netherlands

Department of Development and Regeneration Section Pediatric Neurology University Hospitals KU Leuven Leuven Belgium

Department of Medicine Brigham and Women's Hospital Boston Massachusetts USA

Department of Neurology and Epileptology The Children's Memorial Health Institute and Department of Child Neurology Warsaw Medical University Warsaw Poland

Department of Neurology University of Maryland School of Medicine Baltimore MD USA

Department of Neurosurgery Rudolf Magnus Institute for Neuroscience University Medical Center Utrecht The Netherlands

Department of Pathology Academic Medical Center University of Amsterdam Amsterdam The Netherlands

Department of Pathology and Molecular Medicine 2nd Faculty of Medicine and Motol University Hospital Prague Czech Republic

Department of Pathology University Medical Center Utrecht Utrecht The Netherlands

Department of Pediatric Neurology 2nd Faculty of Medicine and Motol University Hospital Prague Czech Republic

Department of Pediatric Neurology Rudolf Magnus Institute for Neuroscience University Medical Center Utrecht The Netherlands

Department of Pediatrics Medical University Vienna Vienna Austria

Department of Translational Neuroscience Brain Center Rudolf Magnus University Medical Center Utrecht Utrecht The Netherlands

GenomeScan BV Leiden The Netherlands

Institute of Neurology Medical University Vienna Vienna Austria

Pediatric Neurology Unit UZ Brussel Brussels Belgium

Stichting Epilepsie Instellingen Nederland Heemstede The Netherlands

Swammerdam Institute for Life Sciences Center for Neuroscience University of Amsterdam Amsterdam The Netherlands

Systems Medicine Department Child Neurology and Psychiatry Unit Tor Vergata University Hospital of Rome Rome Italy

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Sci Rep. 2022 Sep 14;12(1):15457. doi: 10.1038/s41598-022-20109-7. PubMed

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