Objectif Recent studies have highlighted a strong genetic association between Parkinson’s disease (PD) and Gaucher’s disease (GD), a lysosomal storage disorder that causes severe neurodegeneration in children and shares some pathophysiological features of PD. GD results from mutations that reduce activity of the enzyme glucocerebrosidase (GCase), causing impaired lysosomal function. It was recently shown that GCase mutations cause several defects associated with impaired cellular quality control - impaired autophagy, mitochondrial dysfunction and accumulation of oligomeric alpha-synuclein, a protein strongly involved in sporadic and genetic PD forms. In fact, alpha-synuclein aggregates are the main constituent of Lewy Bodies, characteristic proteins inclusions found in parkinsonian brains. While PD shows similar features and involves defects in the same pathways, it remains unclear how these diverse findings relate to each other.In the present study we propose to identify the specific interactions between intracellular signaling pathways, cellular quality control pathways and alpha-synuclein oligomerization in an attempt to generate a unifying hypothesis that brings together known features of GD and PD pathophysiology. We will use primary neuronal cultures from gba knockout mice and inducible pluripotent stem cells derived from the GD mouse model and from patients, in which alpha-synuclein will be overexpressed or silenced. Mitochondrial (dys)function, impaired clearance mechanisms and alpha-synuclein oligomerization will be quantitatively characterized in these models by means of an array of biochemical, biophysical and advanced imaging techniques. The results of the work will give us further insights into PD molecular mechanisms and may provide new therapeutic targets. Champ scientifique natural scienceschemical sciencesinorganic chemistryalkaline earth metalsmedical and health sciencesmedical biotechnologycells technologiesstem cellsnatural sciencesbiological sciencesgeneticsmutationmedical and health sciencesbasic medicineneurologyparkinsonmedical and health sciencesbasic medicinephysiologyhomeostasis Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Thème(s) MSCA-IF-2014-EF - Marie Skłodowska-Curie Individual Fellowships (IF-EF) Appel à propositions H2020-MSCA-IF-2014 Voir d’autres projets de cet appel Régime de financement MSCA-IF-EF-ST - Standard EF Coordinateur UNIVERSITY COLLEGE LONDON Contribution nette de l'UE € 183 454,80 Adresse GOWER STREET WC1E 6BT London Royaume-Uni Voir sur la carte Région London Inner London — West Camden and City of London Type d’activité Higher or Secondary Education Establishments Liens Contacter l’organisation Opens in new window Site web Opens in new window Participation aux programmes de R&I de l'UE Opens in new window Réseau de collaboration HORIZON Opens in new window Coût total € 183 454,80