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Investigating Parkinson's disease

Mechanisms and consequences of the accumulation of lipid droplets in Parkinson disease

Florence Jollivet, Anissa Souidi

Parkinson disease (PD) is a neurodegenerative disease that is characterized by the accumulation of alpha-Synuclein (aSyn) aggregates, known as Lewy bodies. aSyn is pre-synaptic protein specific of vertebrates, which contains an N-terminal amphipatic domain important for its binding to phospholipidic membranes, such as in synaptic vesicules. aSyn also binds to cellular membranes made of a phospholipid monolayer such as in lipid droplets (LDs), but the physiological role of this interaction remains to be elucidated.

LDs are cellular organelles allowing the storage of neutral lipids such as triacylglycerides (TAGs) or sterol esters. The homeostasis of LDs depends on the equilibrium between lipid biosynthesis or lipolysis controlled by lipases (Figure). Lipases are themselves regulated by perlipins (PLIN) that are LD proteins, binding to LDs. The process that control LD homeostasis are largely conserved between species and Drosophila has appeared as a model of choice to study their regulation and their importance in physiopathology. Professor Ronald Kuhnlein, our collaborator on this project (Graz University, Austria) has pioneered the study of LDs in Drosophila. The great majority of studies on LDs in mammals and Drosophila has focused on adipocytes but recently a growing interest has raised on the study of LDs in the nervous system in several laboratories including ours (Van Den Brink et al 2018). Interestingly for this project on PD, it was shown that the expression of human aSyn induces LD formation in yeast, human and rodent cellular models.  We have  shown that the LD protein dPlin2 cooperate with aSyn to induce LD accumulation in photoreceptor cells of adult Drosophila (Girard et al. 2021). Furthermore, we have shown that the accumulation of LDs promotes an increased resistance of aSyn to mild digestion with proteinase K, which is a signature of aSyn conversion toward pathological forms. In this project we will study the mechanism promoting LD accumulation and elucidate the role of LDs in the progression of PD.

Collaborators:

Ronald Kuhnlein, University of Graz, Austria

Benjamin Dehay, Marie Hélène Canron, IMN, Bordeaux, France

Fundings: France Parkinson, Fondation de France

Past lab members on this project : Daan Van den Brink, Victor Girard, Nathalie Davoust, Gilles Chatelain