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 [Tesi di dottorato] (Unpublished)

[thumbnail of Marzo_Ludovica_24.pdf]
Preview
PDF
Marzo_Ludovica_24.pdf

Download (27MB) | Preview
Item Type: Tesi di dottorato
Resource language: English
Title: Exploring the mechanisms involved in prion degradation and spreading from cell-to-cell in neuronal cell models
Creators:
Creators
Email
Marzo, Ludovica
ludovica.marzo@gmail.com
Date: 30 November 2011
Number of Pages: 230
Institution: Università degli Studi di Napoli Federico II
Department: Biologia e patologia cellullare e molecolare "L. Califano"
Scuola di dottorato: Medicina molecolare
Dottorato: Genetica e medicina molecolare
Ciclo di dottorato: 24
Coordinatore del Corso di dottorato:
nome
email
Nitsch, Lucio
nitsch@unina.it
Tutor:
nome
email
Zurzolo, Chiara
zurzolo@unina.it
Date: 30 November 2011
Number of Pages: 230
Keywords: PrpSc, prion degradation, autophagy, 4-hydroxyl-tamoxifen, lysosomes, cholesterol, tunneling nanotubes, spreading, PrPC, Myosin-X
Settori scientifico-disciplinari del MIUR: Area 05 - Scienze biologiche > BIO/13 - Biologia applicata
Date Deposited: 09 Dec 2011 12:58
Last Modified: 30 Apr 2014 19:48
URI: http://www.fedoa.unina.it/id/eprint/8750
DOI: 10.6092/UNINA/FEDOA/8750

Collection description

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.

Downloads

Downloads per month over past year

Actions (login required)

View Item View Item