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You are here: Home / Teams / Regulated Cell Death and Genetics of Neurodegeneration - B. Mollereau / Research projects / Proteostasis in neurodegenerative diseases

Proteostasis in neurodegenerative diseases

Haixiu Jin, Daan Van Den Brink and Gilles Chatelain

Equilibrated protein homeostasis or proteostasis requires the precise coordination of folding of newly synthetized proteins, quality control and degradative mechanisms and thereby prevent abnormal aggregation of pathological proteins (Hetz and Mollereau 2014, Mollereau et al. 2016). Neurological disorders such as Alzheimer's, Parkinson's, Huntington's, ALS or prion- like diseases have different clinical outcomes but they all share the accumulation of misfolded pathological proteins and are now classified as protein misfolding diseases (PMD). Protein folding mechanisms that include cytoplasmic and endoplasmic reticulum (ER) chaperones permit the proper folding of newly synthetized proteins. One key mechanism is the unfolded protein response (UPR) that takes place within the ER to ensure folding and proteostasis. In our laboratory we have shown that a preconditioning of the ER using genetics or the drug tunicamycin (ER stress inducer by inhibition of glycosylation) triggered the UPR and conferred neuroprotection in Parkinson's disease models in Drosophila, mouse and human neuroblastoma cell lines (Mendes et al. 2009; Fouillet et al. 2012). Precisely, we have shown that UPR stimulation induces a neuroprotective pathway that involves autophagy.
We hypothesize that maintaining a physiological ER stress response could be neuroprotective in Parkinson's disease.  In our group, we propose to understand the underlying mechanisms of ER preconditioning and test their contribution in Drosophila, mouse and human cellular models of Parkinson's disease.