Funded Studies
This grant builds upon the research from a prior grant: The Unfolded Protein Response (UPR) Chaperone GRP78/BiP as a Therapeutic Target for Alpha-Synuclein Toxicity
Promising Outcomes of Original Grant:
The original study validated the role of PERK (protein kinase RNA-like endoplasmic reticulum kinase) signaling in the progression of Parkinson’s disease (PD). We found that PERK signaling is activated in part of the brain called the substantia nigra of pre-clinical models that over-expressed the protein alpha-synuclein and developed PD-like symptoms. This finding is in agreement with recent discovery of the peIF2α and CHOP proteins, hallmarks of the PERK unfolded protein response (a cellular stress response), in postmortem brain tissue of PD patients.
Objectives for Supplemental Investigation:
In this study, we will determine if manipulations with expression of activating transcription factor 4 (ATF4) and CHOP protein in model brain with alpha-synuclein toxicity are beneficial to stop PD progression. This project aims to tease out the exact roles of both proteins in nigral degeneration.
Importance of This Research for the Development of a New PD Therapy:
Successful completion of this study will determine therapeutic targets and accelerate the translation of basic research into clinical studies.
Final Outcome
The PERK protein is active in the brain of pre-clinical models of Parkinson's that over-express alpha-synuclein, the sticky protein that clumps in the brains of people with PD. PERK, along with recently discovered CHOP proteins, are involved in cellular response to stress, in particular, PD-related stress induced by alpha-synuclein. Similarly, activating transcription factor 4 (ATF4) plays a crucial role in the adaptation to stress and activation of the cell's program of death. In this study, we manipulated chemical reactions that take place inside the cell and involve PERK. We aimed to determine the role of ATF4 in mediating the stress response to the excess of alpha-synuclein in the substantia nigra pars compacta, the brain region rich in dopamine-producing nerve cells. We used two different research approaches to uncover the exact roles of ATF4 in the alpha-synuclein model of PD. The first approach revealed that blocking over-production of ATF4 diminishes alpha-synuclein¬¬-induced death of nerve cells. The second approach revealed that ATF4 over-production is toxic. This toxicity is mediated in part by CHOP. In addition to CHOP, one or more currently unidentified cellular mechanisms supporting cell death exists, and this mechanism is mediated by ATF4. This was also confirmed in models lacking CHOP and in models overexpressing alpha-synuclein and lacking both ATF4 and CHOP. Our data suggest that manipulating the production of both ATF4 and CHOP possibly has a therapeutic potential.
April 2016
Presentations & Publications
- Salganik M, Sergeyev VG, Shinde V, et al. The loss of glucose-regulated protein 78 (GRP78) during normal aging or from siRNA knockdown augments human alpha-synuclein (α-syn) toxicity to rat nigral neurons. Neurobiol Aging. 2015;36(6):2213-2223.
- Gully JC, Sergeyev VG, Bhootada Y, et al. Up-regulation of activating transcription factor 4 induces severe loss of dopamine nigral neurons in rat model of Parkinson's disease. Neurosci Lett. 2016;627:36-41.
- Gorbatyuk OS, Sergeyev VG, Gully JC, Gorbatyuk MS, Zolotukhin S, Mendez-Gomez H. The role of activating transcription factor 4 (ATF4) in nigral degeneration induced by human alpha-synuclein cytotoxicity. Presented at: Nanosymposium, Society for Neuroscience Meeting; October 17-27, 2015; Chicago, IL.