CONTROL OF THE CA2+ - NFAT-IL-2 PATHWAY BY LRRK2 IN ASPERGILLUS-STIMULATED DENDRITIC CELLS

Abstract

THE PARKINSON?S DISEASE-ASSOCIATED PROTEIN, LEUCINE-RICH REPEAT KINASE 2 (LRRK2), IS EXPRESSED IN MYELOID CELLS SUCH AS MACROPHAGES AND DENDRITIC CELLS (DCS) AND IS POSSIBLY INVOLVED IN THE HOST IMMUNE RESPONSE AGAINST PATHOGENS. IN THE CONTEXT OF INFLAMMATORY BOWEL DISEASE, LRRK2, TOGETHER WITH THE NCRNA REPRESSOR OF THE NUCLEAR FACTOR OF ACTIVATED T CELLS (NFAT) (NRON) REPRESENTS A NEGATIVE REGULATOR OF NFAT. THIS PROJECT INVESTIGATES LRRK2 AND THE CALCINEURIN/NFAT PATHWAY IN DCS THROUGH DECTIN STIMULATION BY A-1,3 ? GLUCAN AND GERMINATING ASPERGILLUS FUMIGATUS MORPHOTYPES. LRRK2 LEVELS WERE FOUND TO BE MODULATED IN DCS, POSSIBLY THROUGH DEGRADATION OF LRRK2 BY NON-CANONICAL AUTOPHAGY INDUCED BY FUNGI. THE DEGRADATION OF LRRK2 BY AUTOPHAGY WAS FURTHER INVESTIGATED BY LOOKING AT LRRK2 EXPRESSION IN LYSOSOMES OF DCS AND BY ELECTRON MICROSCOPY. IN ADDITION, COMPONENTS OF THE NRON COMPLEX WERE KNOCKED DOWN IN DCS TO SEE HOW THIS AFFECTS DC CYTOKINE RESPONSE.