Modulating Ire1 to treat Parkinson's Disease – Ire1-PD

We have analyzed the response of Drosophila submitted to tunicamycin and paraquat (a pesticide that induce Parkinson hallmarks). By using mutant files, we are testing the contribution of specific factors in protection against paraquat

We have found a novel protective pathway that protect the organism against the exposure to paraquat. Using Drosophila mutant for p53, we have shown that tunicamycin induces a p53-dependent protective mechanism. Moreover, we found that p53 activates autophagy that is known to clear toxic agregates in Parkinson disease.

Together, our project will elucidate the underlying mechanisms involved in ER mediated protection and prompt further studies to develop therapy to halt Parkinson disease progression.

1-1-Pocas GM, Branco-Santos J, Herrera F, Outeiro TF, Domingos PM. (2015) Alpha-Synuclein modifies mutant huntingtin aggregation and neurotoxicity in Drosophila. Human Molecular Genetics. Apr 1;24(7):1898-907.
2-1-Mollereau B. (2015) Colling-induced ER stress is Good for your Brain. EBioMedicine. May 9;2(6):482-3.
3-Hetz C and Mollereau B (2014). Disturbance of ER proteostasis in neurodegenerative diseases. Nature Review Neurosciences. Apr;15(4):233-49.
4-Mollereau B, Manié S and Napoletano F. (2014) Getting the better of ER stress. Journal of Cell Communication and Signaling Dec;8(4):311-21. doi: 10.1007/s12079-014-0251-9..
5- Michel PP, Hirsch EC, Hunot S. (2016) Understanding Dopaminergic Cell Death Pathways in Parkinson Disease. Neuron. 90:675-91
6-Mollereau B, Rzechorzek NM,...Domingos PM, Hunot S... et al. (2016) Adaptive Preconditioning in Neurological Diseases – Therapeutic Insights from Proteostatic Perturbations. Brain Research. Mar 2. pii: S0006-8993(16)30092-0. doi: 10.1016/j.brainres.2016.02.033

Parkinson’s Disease (PD) is a devastating neurodegenerative disease, which affects a growing number of patients in Europe. The lack of treatment for patients, who rapidly become disabled, brings high social and economic burdens for families and society. Despite numerous studies on PD, scientific research is still behind in term of strategies to halt disease progression. In our project, we will explore novel and promising protective mechanisms to reduce the pathological hallmarks in models of PD. We have recently shown that mild Endoplasmic Reticulum (ER) stress (ER preconditioning), by tunicamycin (Tm) treatment, induces the unfolded protein response (UPR), which results in neuronal protection in cellular and animal models of PD (Fouillet et al. 2012). In four specific tasks, we propose a unique approach at the whole organism (Drosophila and mice) and cellular levels (human neuroblastoma cells) to understand the underlying mechanisms of tunicamycin-mediated protection in PD. The first task will be dedicated to the coordination of the program. In the second task, partner 1, 2 and 3 will establish the contribution of xbp-1-independent protection that is mediated by Ire1 in models of PD (Drosophila and mouse PD models as well as human cell lines). Partner 1 and Partner 2 will use the Drosophila a-Synuclein (a-Syn) model and test if the protection mediated by Tm is dependent on Ire1 and/or xbp1. Partner 3 will use the MPTP model and test if Tm treatment reduces dopaminergic (DA) death and locomotor dysfunction associated with the subchronic treatment of MPTP and if Tm mediated protection requires Ire1 independently of xbp1. Partner 1 will use SH-SY5Y cells treated with MPP+ and determine the contribution of Ire1 versus xbp1 in Tm-mediated protection. In the third task, Partner 1, 2 and 3, will determine if Tm can restore defective autophagy caused by a-Syn expression and MPTP treatment and study the role of autophagy in a-Syn aggregate clearance and DA neuron viability. In the fourth task, Partner 1, 2 and 3 will study the role of specific Regulated Ire1-dependent decay (RIDD) targets in Tm-mediated neuroprotection. This will involve monitoring by quantitative RT-PCR if the levels of specific RIDD targets, such as indy/ SLC13A3, sparc/SPARC and fatp/FAT1/4, are regulated in Drosophila and mammalian models of PD. We will also test directly the role of these RIDD targets in Tm mediated protection by doing assays in the presence of RNAi for these specific RIDD targets. This is a unique approach to precisely identify the mechanisms by which ER stress protects from neurodegeneration in PD models. The long-term objective of this project is to open therapeutic perspectives for PD patients.