CATABOLIC SIALIDASES

Understanding the roles of mammalian sialidases in glycolipid catabolism

Coordinatore	IZMIR INSTITUTE OF TECHNOLOGY    more  Organization address address: Gulbahce URLA city: IZMIR postcode: 35430 contact info Titolo: Prof. Nome: Ahmet Cognome: Koc Email: send email Telefono: 902328000000 Fax: 902328000000
Nazionalità Coordinatore	Turkey [TR]
Totale costo	100˙000 €
EC contributo	100˙000 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2010-RG
Funding Scheme	MC-IRG
Anno di inizio	2011
Periodo (anno-mese-giorno)	2011-04-01   -   2015-03-31

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	IZMIR INSTITUTE OF TECHNOLOGY  Organization address address: Gulbahce URLA city: IZMIR postcode: 35430 contact info Titolo: Prof. Nome: Ahmet Cognome: Koc Email: send email Telefono: 902328000000 Fax: 902328000000	TR (IZMIR)	coordinator	100˙000.00

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 Obiettivo del progetto (Objective)

'Sialidases are widely distributed in nature, from microorganisms to mammals. Mammalian sialidases differ in their tissue distribution, subcellular localization, substrate specificity and pH optimum. To date, several mammalian sialidases have been cloned; a lysosomal form (Neu1), a cytosolic form (Neu2), a plasma membrane-associated form (Neu3) and a lysosomal/mitochondrial form (Neu4). Defining the functional impact of sialidases on complex physiological and cellular processes should uncover the biological significance of sialidase-susceptible sialic acids on glycoproteins and glycolipids. Our goal has been to clarify biological functions of mammalian sialidases. Recently we investigated the role of lysosomal/mitochondrial sialidase Neu4 in glycolipid degradation using mouse model with the combined deficiency of β-hexosaminidase A (HexA) and sialidase Neu4. Our mouse model progressed toward the neuropathological abnormalities of human Tay-Sachs patients. The appearance of epileptic seizures and increased glycolipid storage demonstrated the predicted increased severity of disease indicative of the importance of Neu4 in glycolipid degradation but it is clear from the much milder than expected phenotype that other sialidases such as Neu1 and Neu3 also contribute to catabolism reactions. We now propose to investigate the intralysosomal mechanism by which glycolipids are degraded by sialidase Neu1 using mouse models. Therefore, the main objectives of this proposal are: (1) to generate first Neu1-/- knockout mouse models (2) to generate Neu1-/-HexA-/- (3) to generate Neu1-/-Neu4-/-HexA-/- triple knockout mouse models. If successful, our studies will significantly increase the state of knowledge of sialidase contribution in glycolipid degradation and can suggest new therapeutic approaches for Tay-Sachs disease based on the Neu1 and Neu4-catalyzed metabolic bypath.'