A NOVEL LINK BETWEEN CELLULAR STRESS AND NEURODEGENERATION

MARCELO PÉREZ-PEPE; LETICIA INÉS LAROTONDA; PABLO LA SPINA; MAXIMILIANO J KATZ; ANA FERNÁNDEZ-ÁLVAREZ; PABLO WAPPNER; GRACIELA LIDIA BOCCACCIO

Ciudad autónoma de Buenos Aires

Congreso; REUNIÓN CONJUNTA DE SOCIEDADES DE BIOCIENCIAS; 2017

Cellular stress is a common feature in diverse pathologies, including cancer and neurodegeneration. Several stress factors, including oxidants and unfolded proteins trigger a global translational shutdown, while the translation of protective proteins is facilitated. Quite recently, independent work from several labs including ours indicates that mRNAs that aren?t translated during the stress response form large cytoplasmic aggregates termed Stress Granules (SGs).SG formation is conserved in mammalian, insects, yeasts, trypanosomes and plants. SGs are transient and highly dynamic and their contribution to the stress-induced translational reprogramming or to cell survival remains unknown. Understanding SG composition and dynamics will help to unveil their regulation and relevance. To identify the signaling pathways that regulate SG formation and dissolution we performed a loss-of-function screen in Drosophila cells. We developed BUHO, a MATLAB script for image analysis and we identified 21 positive and 16 negative modulators of SG dynamics (Z-Score > 2). We decided to focus on Leucine Rich Repeat Kinase (dLRRK), given that mutations in the human homolog hLR-RK2 are causative of Parkinson disease, which has not been linked to SG formation previously. We found that the knock down of dLRRK or hLRRK2 enhances SG formation. Experiments in human cell lines and fly brains indicate that LRRK dysfunction leads to the accumulation of ubiquitinated protein and provokes proteotoxic stress(p