APPERAD

Regulation of APP Metabolism by ER-Associated Degradation

Coordinatore	HELSINGIN YLIOPISTO    more  Organization address address: YLIOPISTONKATU 4 city: HELSINGIN YLIOPISTO postcode: 14 contact info Titolo: Ms. Nome: Anna Cognome: Mattila Email: send email Telefono: +358 9 191 57622 Fax: 358919000000
Nazionalità Coordinatore	Finland [FI]
Totale costo	75˙000 €
EC contributo	75˙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-2007-4-3-IRG
Funding Scheme	MC-IRG
Anno di inizio	2008
Periodo (anno-mese-giorno)	2008-03-01   -   2011-02-28

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	HELSINGIN YLIOPISTO  Organization address address: YLIOPISTONKATU 4 city: HELSINGIN YLIOPISTO postcode: 14 contact info Titolo: Ms. Nome: Anna Cognome: Mattila Email: send email Telefono: +358 9 191 57622 Fax: 358919000000	FI (HELSINGIN YLIOPISTO)	coordinator	0.00

Mappa

 Word cloud

Esplora la "nuvola delle parole (Word Cloud) per avere un'idea di massima del progetto.

 Obiettivo del progetto (Objective)

'The pathological Ab peptide that accumulates in senile plaques in Alzheimer’s disease (AD) brains is derived from a precursor protein APP. Although etiology of AD is complex, genetic evidence shows that duplication of the APP gene locus leading to elevated levels of APP protein is sufficient to cause early-onset AD highlighting the importance of regulatory mechanisms. The events resulting in generation of Ab from APP are well characterized but the regulation of APP protein levels in cells is poorly understood. Previous studies suggest that a degradation pathway in the ER participates in the regulation of APP metabolism but the exact mechanism remains unknown. Recently, we have identified APP as a substrate for ER-associated degradation pathway (ERAD). Here, we will focus on characterization of the ERAD pathway of APP aiming at (1) identification of ERAD proteins that associate with APP, and (2) characterization of regulatory mechanisms that control ERAD of APP. We have identified an APP-binding protease HtrA2 that collaborates with the proteasome in ERAD of APP. Importantly, HtrA2-/- mice display a neurodegenerative phenotype and cells derived from these mice are increasingly susceptible to ER stress while secreting more Ab. Currently, there are no methods available for analyzing HtrA2 protease activity in cells and tissues. We will develop a fluorescence-based assay for HtrA2 activity to facilitate mechanistic studies linking HtrA2 to neurodegeneration. Modulation of APP metabolism in the early secretory pathway is an attractive therapeutic approach as it precedes other APP proteolytic processing events. Enhancement of ERAD could be used to downregulate APP metabolism and help the aging neurons in their battle against protein aggregation stress. Thus, the aims of this proposal are (1) to determine the role of ERAD as a catabolic pathway regulating APP levels and (2) to assess if changes in proteolytic activity of HtrA2 play a role in the pathogenesis of AD.'