Orsolya Kapuy1, Marianna Holczer1, Gábor Bánhegyi1
1 Semmelweis University, Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Budapest
Introduction: Loss of cellular protein homeostasis is characterized by the appearance of protein aggregates; those are common features of aging and several neurodegenerative diseases, such as fatal Parkinson’s disease and Huntington’s disease. Novel data suggest that intensive autophagy-dependent self-cannibalism might extend viability. Some results suppose that a proper Gadd34-regulated AMPK-mTOR balance has a crucial role in controlling life-and-death decision upon neurodegenerative diseases. Nevertheless the exact molecule which executes the cellular switch between life and death is not known yet.
Aims: We claim that Gadd34 is the key sensor molecule to guarantee the appropriate choice between the autophagy-dependent survival and the self-killing mechanisms in response to cellular stress. Our hypothesis is that Gadd34 ensures the proper dynamical features of the regulatory system via negative and positive (or double negative) feedback loops. Our goal is to discover novel compounds which can extend cell viability upon neurodegenerative disease.
Methods: Our scientific questions are approached from a systems biological perspective by using both molecular biological techniques and theoretical biological tools. To explore the key regulatory loops the experiments are carried out in human cell lines, meanwhile the kinetic features of decision making process are tested by computer simulations.
Results: We find a proper concentration of mTOR inhibitors/AMPK activators (i.e. EGCG, the polyphenol of green tee) when cell viability can be extended via autophagy, meanwhile cell death gets postponed upon endoplasmic reticulum stress. This positive effect of mTOR inhibitors/AMPK activators on cell viability is achieved via Gadd34 regulation. We generate a wiring diagram of the control network and elaborate a mathematical model which is able to describe the dynamical features of this network of life-and-death decision in cellular stress.
Conclusion: We verify that extended cell viability induced by mTOR inhibitors/AMPK activators is managed through Gadd34-dependent autophagy.
This work was supported by the ÚNKP-17-4-III-SE-75 New National Excellence Program of the Ministry of Human Capacities.