DATROPHIN · A Drosophila Model for Dentatorubropallidoluysian Atrophy
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2004-03-01 → 2005-02-28
- EU contribution
- €39,691
- Participants
- 1
- Scheme
- EIF
Lines connect the coordinator with its partners.
Results in brief
Final Activity Report Summary - DATROPHIN (A Drosophila Model for Dentatorubropallidoluysian Atrophy)
Dentatorubropallydoluisian atrophy is a neurodegenerative disease caused in humans by the atrophin-1 protein. In the diseased condition a stretch of 14 glutamines is expanded up to 70 by genetic instability of this repeat. The drosophila ortholog of atrophin-1 is atro, a multi-faceted protein involved in several cellular and developmental processes. During the year covered by the European reintegration grants (ERG) we focussed on studying the role of atro in important signalling pathways and found out that it acted as a negative regulator of the notch signalling pathway by inhibiting activation of transcription by the notch intracellular domain. We also expanded the glutamine stretches in the atro protein in order to mimic the diseased conditions and see if the modified protein retained all the functions of the normal one. Nevertheless, all the transgenic flies we generated expressed very little, if any, modified protein. By the time of the project completion we were analysing all the possible problems, however initial studies suggested that the proteins were quickly degraded by the cells where they were expressed.
Data: CORDIS, © European Union
Project objective
Using Drosophilae way aim to a detailed and comprehensive knowledge of the physic-pathological role of Atrophies proteins, linked to dentatorubropallidoluysian atrophy (DRPLA).Neurodegenerative diseases due to polyglutamine expansion are a growing family of diseases affecting a consistent percentage of the population. They bear an enormous emotional impact for patients even before their onset and represent a considerable economic burden for society. DRPLA is caused by the expansion of a polyglutamine tract in the Atrophic-I protein. Recently, Drosophilae Atrophic has been identified, shown to encode a transcriptional co repressor and to be involved in several diverse processes from embryonic segmentation to eye development. The role Atrophic in the eye, the availability of several developmental assays, of a series of independently isolated mutations and other useful materials is unprecedented in the history of the use of Drosophilae to study neurodegeneration. We will engineer flies expressing the wild type and modified versions of Drosophilae Atrophic and the wild type and mutated human atrophic-I gene. We will then carry out genetic screens for modifiers of a rough eye phenotype and characterise the integrators for the role the may have in both the physiological and pathological functions of Atrophies. We will also use a genome-wide approach to monitor transcriptional regulation by Atrophies, eventual alterations due to polyglutamine expansions and their role in neurodegeneration. We expect to identify factors important for the normal regulations of the Atrophies, and that may be involved in signalling pathways that modify gene expression through Atrophies. In particular we aim to identify key factors for the role of Atrophies in DRPLA, to understand the peculiarity of the mutant proteins and determine the aberrant processes underling cellular pathology.
Original text from CORDIS.
Participants
- FONDAZIONE CENTRO SAN RAFFAELE DEL MONTE TABOR · MILANOCoordinatorItaly
Links
Data: CORDIS, © European Union