NEURONAD

Isoform-specific functions of NAD-synthesising enzyme NMNAT in compartmentalised neuronal death

Coordinatore	THE UNIVERSITY OF NOTTINGHAM    more  Organization address address: University Park city: NOTTINGHAM postcode: NG7 2RD contact info Titolo: Mr. Nome: Paul Cognome: Cartledge Email: send email Telefono: +44 115 8466757 Fax: +44 115 9513633
Nazionalità Coordinatore	United Kingdom [UK]
Totale costo	270˙145 €
EC contributo	270˙145 €
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-2011-IEF
Funding Scheme	MC-IEF
Anno di inizio	2012
Periodo (anno-mese-giorno)	2012-08-01   -   2014-07-31

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	THE UNIVERSITY OF NOTTINGHAM  Organization address address: University Park city: NOTTINGHAM postcode: NG7 2RD contact info Titolo: Mr. Nome: Paul Cognome: Cartledge Email: send email Telefono: +44 115 8466757 Fax: +44 115 9513633	UK (NOTTINGHAM)	coordinator	270˙145.80

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 Obiettivo del progetto (Objective)

'Nicotinamide mononucleotide adenylyltransferase (NMNAT) is the central enzyme in NAD biosynthetic pathways. Among the three known mammalian isozymes, nuclear NMNAT1 generates NAD which is used as substrate for the enzymes SIRT1 and PARP1, involved in transcription control and DNA damage repair and associated to cell death and senescence. Various data suggest that NMNAT1 could be neuroprotective: SIRT1 activation or overexpression confers neuroprotection in various models of neurodegenerative diseases; PARP1 mild activation is neuroprotective; finally, the overexpression of NAMPT, an enzyme producing an NMNAT substrate, also confers neuroprotection. However, NMNAT1 requirement for neuron maintenance has not yet been directly demonstrated. NMNAT2 instead, located prevalently in the cytoplasm in association with the Golgi apparatus, acts as a survival factor for axons and synapses, which degenerate when NMNAT2 is rapidly degraded after an injury. NMNAT enzyme activity is necessary for axon protection, but the mechanism involved is still unclear. These data led us to the hypothesis that NMNAT activity is required for the survival of distinct neuronal compartments and that the two isoforms NMNAT1 and NMNAT2 locally provide for this activity in the cell nucleus and in the axon, respectively. This project will combine the enzymology skills of the IEF applicant with the neurobiology and molecular genetics expertise of the host laboratory to test this hypothesis by generating a neuron-specific conditional knockout (KO) mouse for NMNAT1 using the Cre-loxP system and by studying the mechanism of NMNAT2-mediated neuroprotection in primary neurons. Our results will identify NMNAT enzymes as targets for pharmacological intervention in neurodegeneration. This study will be achieved by the mobility of the IEF fellow, who will acquire as a result a combination of disciplines and techniques key to his career development as an independent scientist.'

Introduzione (Teaser)

Europe presents an increasing prevalence of psychiatric and neurodegenerative disorders. Insight into the underlying aetiology is of paramount importance to design new therapies.