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.

Mills, J.d., Iyer, A.m., Van Scheppingen, J., Bongaarts, A., Anink, J.j., Janssen, B., et al. (2017). Coding and small non-coding transcriptional landscape of tuberous sclerosis complex cortical tubers: Implications for pathophysiology and treatment. SCIENTIFIC REPORTS, 7(1), 8089 [10.1038/s41598-017-06145-8].

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

Curatolo P.;
2017

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.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/39 - Neuropsichiatria Infantile
English
Con Impact Factor ISI
Mills, J.d., Iyer, A.m., Van Scheppingen, J., Bongaarts, A., Anink, J.j., Janssen, B., et al. (2017). Coding and small non-coding transcriptional landscape of tuberous sclerosis complex cortical tubers: Implications for pathophysiology and treatment. SCIENTIFIC REPORTS, 7(1), 8089 [10.1038/s41598-017-06145-8].
Mills, Jd; Iyer, Am; Van Scheppingen, J; Bongaarts, A; Anink, Jj; Janssen, B; Zimmer, Ts; Spliet, Wg; Van Rijen, Pc; Jansen, Fe; Feucht, M; Hainfellner, Ja; Krsek, P; Zamecnik, J; Kotulska, K; Jozwiak, S; Jansen, A; Lagae, L; Curatolo, P; Kwiatkowski, Dj; Jeroen Pasterkamp, R; Senthilkumar, K; Von Oerthel, L; Hoekman, Mf; Gorter, Ja; Crino, Pb; Muhlebner, A; Scicluna, Bp; Aronica, E
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/192094
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