Exploring the mechanisms involved in prion degradation and spreading from cell-to-cell in neuronal cell models

Marzo, Ludovica (2011) Exploring the mechanisms involved in prion degradation and spreading from cell-to-cell in neuronal cell models. [Tesi di dottorato] (Inedito)

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Transmissible spongiform encephalopathies (TSE), also known as prion diseases, are fatal neurodegenerative disorders present both in human and animals with different aetiology as they can occur genetically, spontaneously or by infection (Prusiner 1998). TSE are caused by the presence of proteinacious aggregates, called ‘prions’, in brains of afflicted individuals. According to the ‘protein-only’ hypothesis, the central event of prion pathogenesis is the conformational change of the cellular protein, PrPC, into its pathological counterpart, PrPSc in a process in which PrPSc acts as a template (Prusiner 1998). Differently from PrPC, mainly constitutes of α-helices, PrPSc is enriched in β-sheets, aggregation-prone and resistant to treatment with proteinase K. Despite the intense research, many questions in prion biology are still open related to both the physiological functions of PrPC and mechanism of the disease caused by the misfolded form PrPSc. Thus, exploring some of these aspects at the molecular and cellular level is of fundamental importance for a better understanding of these fatal disorders and for developing potential therapeutical approaches. However, due to the lack of PrPSc-specific antibodies, PrPSc cellular trafficking, production and degradation are poorly defined. In the first part of my thesis I investigated the role of autophagy in prion disease. I demonstrated that although autophagic pathway is stimulated by prion infection, it is not involved in prion degradation. Furthermore, I showed that tamoxifen and its metabolite 4-hydroxil-tamoxifen (OHT) (previously shown to be autophagy inducers) reduce scrapie burden by redistributing cholesterol and PrP to lysosomes in an autophagy-independent manner. These data confirm the role of the lysosomal pathway in prion degradation and of cholesterol in prion formation. Furthermore, since tamoxifen is a wide-available pharmaceutical tool it might have potential application in therapy for prion disease. Another important question in prion biology is related to the spreading of PrPSc. At the different stages of its lethal journey to the central nervous system, PrPSc is transferred from one cell to another and this passage can involve several mechanisms. Recently our laboratory has shown that PrPSc hijacks intercellular membranous channels, called tunneling nanotubes (TNT), for intercellular spread (Gousset et al., 2009; Langevin et al 2009). Therefore, in the second part of my PhD work I have better characterized TNT-mediated trafficking of PrPSc between neuronal cells, as model of prion infection. I also identified factors that could be involved in TNT formation and in the resulting transfer of PrPSc between cells. These results will contribute to the characterization of both TNT formation and prion spreading and open the way to further investigations.

Tipologia di documento:Tesi di dottorato
Parole chiave:PrpSc, prion degradation, autophagy, 4-hydroxyl-tamoxifen, lysosomes, cholesterol, tunneling nanotubes, spreading, PrPC, Myosin-X
Settori scientifico-disciplinari MIUR:Area 05 Scienze biologiche > BIO/13 BIOLOGIA APPLICATA
Coordinatori della Scuola di dottorato:
Coordinatore del Corso di dottoratoe-mail (se nota)
Nitsch, Lucionitsch@unina.it
Tutor della Scuola di dottorato:
Tutor del Corso di dottoratoe-mail (se nota)
Zurzolo, Chiarazurzolo@unina.it
Stato del full text:Accessibile
Data:30 Novembre 2011
Numero di pagine:230
Istituzione:Università di Napoli Federico II
Dipartimento o Struttura:Biologia e patologia cellullare e molecolare "L. Califano"
Stato dell'Eprint:Inedito
Scuola di dottorato:Medicina molecolare
Denominazione del dottorato:Genetica e medicina molecolare
Ciclo di dottorato:24
Numero di sistema:8750
Depositato il:09 Dicembre 2011 13:58
Ultima modifica:29 Maggio 2012 12:58

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