Molecular bases of Down syndrome: differential gene expression and pathway dysregulation associated with trisomy 21

Granese, Barbara (2011) Molecular bases of Down syndrome: differential gene expression and pathway dysregulation associated with trisomy 21. [Tesi di dottorato] (Inedito)

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Abstract

Down syndrome (DS) is known to be a complex disorder caused by trisomy of either the entire or a critical portion of chromosome 21 (21q22.1-22.3), but the pathophysiologic bases of the clinical DS phenotypes are still obscure. A previous genome-wide analysis performed on DS and euploid lymphoblastoid cell lines, allowed us to identify genes and pathways dysregulated in DS subjects with the aim to expand the knowledge on the molecular bases of DS and to provide new tools for the development of innovative therapeutic approaches. Our results identified ubiquitin mediated proteolysis as the pathway most influenced by trisomy 21, whereas ubiquitin metabolism and regulation of NFkappaB cascade resulted to be two of the most significant down regulated GO categories. On the basis of these results and of the data present in the literature, we analyzed, both to validate microarray data and to investigate their role in DS pathogenesis: the ubiquitin-proteasome system (UPS); the NFkappaB pathway and the DYRK1A/DSCR1/NFAT pathway. Finally, the sequencing analysis of the MCPH1 gene, a causative gene of primary microcephaly deregulated in our DS subjects, in a population of unrelated patients with primary microcephaly. Results suggested that in DS there is a defective protein degradation system that could result from a primary dysfunction of UPS and from an excess of damaged proteins, and in agreement a down-regulation of the NF-kappaB cascade, a model protein regulated by ubiquitination. Finally, also the NFAT pathway resulted deregulated with the overexpression of the two chr21 genes, DYRK1A and DSCR1, and a significant reduction of NFATc2 and its nuclear export. In conclusion, the present study provides evidence of multiple and linked biological processes that have the rational to be directly involved in DS. Therefore, further analyses of these altered genes and pathways could be taken into account

Tipologia di documento:Tesi di dottorato
Parole chiave:Down syndrome, proteasome, NFAT
Settori scientifico-disciplinari MIUR:Area 06 Scienze mediche > MED/38 PEDIATRIA GENERALE E SPECIALISTICA
Coordinatori della Scuola di dottorato:
Coordinatore del Corso di dottoratoe-mail (se nota)
Pignata, Claudio
Tutor della Scuola di dottorato:
Tutor del Corso di dottoratoe-mail (se nota)
Generoso, Andria
Stato del full text:Inedito
Data:30 Novembre 2011
Numero di pagine:110
Istituzione:Università di Napoli Federico II
Dipartimento o Struttura:Pediatria
Stato dell'Eprint:Inedito
Scuola di dottorato:Medicina clinica e sperimentale
Denominazione del dottorato:Riproduzione, sviluppo e accrescimento dell'uomo
Ciclo di dottorato:24
Numero di sistema:8788
Depositato il:07 Dicembre 2011 12:33
Ultima modifica:30 Maggio 2012 13:41

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