Izzo, Antonella (2010) Functional and molecular effects of chromosome 21 trisomy. [Tesi di dottorato] (Inedito)

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Tipologia del documento:	Tesi di dottorato
Lingua:	English
Titolo:	Functional and molecular effects of chromosome 21 trisomy
Autori:	Autore Email Izzo, Antonella antonella.izzo@unina.it
Data:	30 Novembre 2010
Numero di pagine:	90
Istituzione:	Università degli Studi di Napoli Federico II
Dipartimento:	Biologia e patologia cellullare e molecolare "L. Califano"
Scuola di dottorato:	Medicina molecolare
Dottorato:	Patologia e fisiopatologia molecolare
Ciclo di dottorato:	23
Coordinatore del Corso di dottorato:	nome email Avvedimento, Vittorio Enrico avvedim@unina.it
Tutor:	nome email Nitsch, Lucio nitsch@unina.it
Data:	30 Novembre 2010
Numero di pagine:	90
Parole chiave:	Down Syndrome; mitochondria; stem cells.
Settori scientifico-disciplinari del MIUR:	Area 06 - Scienze mediche > MED/03 - Genetica medica Area 06 - Scienze mediche > MED/04 - Patologia generale
Depositato il:	10 Dic 2010 10:37
Ultima modifica:	30 Apr 2014 19:45
URI:	http://www.fedoa.unina.it/id/eprint/8299
DOI:	10.6092/UNINA/FEDOA/8299

Abstract

Down Syndrome (DS) is the most frequent autosomal aneuploidy that is compatible with post-natal life. The DS phenotype has been attributed to overexpression of chromosome 21 (Hsa21) genes. It is unknown which, and how many, chromosome 21 genes are responsible for each DS phenotypic sign such as mental retardation, cardiac defects, muscle hypotonia, immunological disorders, etc. Hsa21 trisomy has been associated to mitochondrial dysfunction in several DS cells and mouse models suggesting that a mitochondrial dysfunction contributes to DS phenotype. We demonstrated, by microarray analysis and by qRT-PCR, the global upregulation of Hsa21 genes and the dysregulation of genes located on other chromosomes in trisomic fetal hearts at 18-22 weeks of gestation. Downregulation of genes encoding mitochondrial enzymes was a hallmark of trisomic fetal samples. Molecular, functional and morphological studies of mitochondria in primary lines of fetal fibroblasts were performed in order to evaluate the mitochondrial dysfunction associated to the dysregulation of mitochondrial gene expression in DS. Molecular analysis of trisomic fibroblasts demonstrated that the upregulation of chromosome 21 genes and the dysregulation of mitochondrial genes also occur in these cells, and that it is not identical to the one observed in fetal hearts. Functional studies demonstrated a significant reduction of the oxygen consumption rate and of respiratory chain complex I activity in trisomic fibroblasts, a decrease of mtDNA copy number and an increased production of reactive oxygen species. Furthermore, the mitochondria ultrastructure of trisomic fibroblasts, assessed by electron microscopy, revealed morphological abnormalities like giant mitochondria with irregular shape, evident breaks of both inner and outer membranes and an altered cristae pattern. These results are indicative of a widespread mitochondrial dysfunction in DS. To detect the earliest changes in gene expression profile, a new in vitro cell culture model was set up. Human stem cells from euploid as well as from Hsa21 trisomic fetuses were obtained. Both fresh and frozen amniotic fluid cultures were successfully used and the lines obtained appear to be suitable to study the differentiation processes in trisomic vs. euploid cells.

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