Annunziata, Fabio (2014) Therapeutic approaches to Lysosomal Storage Disorders: the example of Pompe Disease. [Tesi di dottorato]


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Item Type: Tesi di dottorato
Resource language: English
Title: Therapeutic approaches to Lysosomal Storage Disorders: the example of Pompe Disease
Date: 26 January 2014
Number of Pages: 108
Institution: Università degli Studi di Napoli Federico II
Istituzioni (extra): CEINGE  Biotecnologie Avanzate, TIGEM – Telethon Insitute of Genetics and Medicine
Scuola di dottorato: SEMM – European School of Molecular Medicine
Dottorato: PhD in Molecular Medicine (Molecular Oncology or Human Genetics)
Ciclo di dottorato: 25
Coordinatore del Corso di dottorato:
Cosma, Maria
Date: 26 January 2014
Number of Pages: 108
Keywords: Lysosomal Storage Disorders, Gene Therapy, SNARE, Autophagy, TFEB
Settori scientifico-disciplinari del MIUR: Area 05 - Scienze biologiche > BIO/11 - Biologia molecolare
Area 05 - Scienze biologiche > BIO/18 - Genetica
Area 06 - Scienze mediche > MED/03 - Genetica medica
Aree tematiche (7° programma Quadro): BIOTECNOLOGIE, PRODOTTI ALIMENTARI E AGRICOLTURA > Scienze della vita, biotecnologia e biochimica per prodotti e processi non-alimentari sostenibili
Additional information: Ciclo VII/XXV, Curriculum Human Genetics
Date Deposited: 11 Feb 2014 14:59
Last Modified: 20 Jan 2015 12:08

Collection description

Lysosomal Storage Disorders (LSDs) are different inherited diseases caused by the deficit of lysosomal or non-lysosomal proteins, resulting in the accumulation of undegraded substrates in lysosomes. Recent studies support the idea that LSDs are associated with a global impairment of the entire endo-lysosomal compartment, specifically of autophagy involved in the principal lysosome-related degradative pathway. However little is known about the mechanisms underlying such dysfunction. Identification of these mechanisms is crucial for the development of precisely targeted therapies for LSDs. In this work I demonstrate that secondary accumulation of cholesterol on lysosomal membranes is the principal molecular mechanism at the basis of lysosomal and autophagosomal dysfunction, as it affects the fusogenic ability of lysosomal membranes. Specifically cholesterol overload affects the distribution and function of SNARE proteins, a protein superfamily involved in fusing vesicular membranes with targeted lysosomal membranes. In addition I propose a novel gene therapy approach for the treatment of Pompe Disease, an LSD characterized by glycogen accumulation. This approach relies on the AAV-mediated over-expression of the TFEB gene, a master regulator for lysosomal-autophagosomal biogenesis that is able to partially rescue the lysosomal glycogen storage by increasing the functionality of the lysosomal-autophagosomal pathway.


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