Project title

S-Glutathionylation in Parkinson’s disease

Scientific Coordinator's name:

Maria João Gama

Scientific Coordinator's e-mail:

mjgama@ff.ul.pt

Principal R&D Unit:

iMed.UL/FFUL

Other R&D Units involved in the project:

-

Project keyword(s)

Glutathione S-transferase pi; S-Glutathionylation; MPTP; TUDCA; ER-stress; PERK-Nrf2/Keap1 pathway; Parkinson’s disease

Short abstract and comments

In this project we hypothesize that (a) GSTP expression may be modified by ER-stress induction through a mechanism involving Nrf2, and that this transcriptional up-regulation could be important in the cytoprotective response to MPTP-induced oxidative stress; and that (b) under stress insults, changes in Nrf2 activity could shift the balance of GSTP involvement in the forward S-glutathionylation reaction that in turn may lead to the establishment of different patterns of post-translational modifications in important regulatory proteins, namely the mediators of PERK – Nrf2 pathway. The immediate objectives of this project are: (a) characterize the effects of the MPTP insult on the ER stress response in C57BL/6 wt and GSTP null mice brain; (b) examine the role of S-glutathionylation in the PERK – Nrf2 pathway; and (c) evaluate the potential neuroprotective effect of TUDCA on MPTP oxidative - driven ER stress. The overall experimental approach proposed should provide new insights into the involvement of UPR and S-glutahionylation in the pathogenesis of PD, and explore possible novel therapeutic strategies to reduce the oxidative load in dopaminergic cells that may be beneficial in slowing the progression of this neurodegenerative disease.

Potential uses/indications

Identification of putative novel antioxidant targets in neuroprotection.