Modelling Neurodegeneration
Oxidative stress, the cellular imbalance between the generation and scavenging of reactive oxygen species (ROS), is emerging as a common denominator of many (age-dependent) debilitating disorders including neurodegenerative diseases like stroke, ALS, Alzheimer’s disease and Parkinson’s disease. Increased levels of ROS, impaired ROS regulating systems and oxidatively modified proteins, lipids and DNA are all hallmarks of post-mortem brain tissues from Alzheimer’s, Parkinson’s and ALS patients. Although previously thought to be indiscriminate, oxidative stress-dependent cell death appears to frequently occur in a programmed fashion (see also Fig. 1). The recent revelation - that ROS cause cell death through distinct cell death signalling pathways - allows to specifically inhibit these cell death signaling cascades to alleviate collective neurodegenerative disease.
On the other hand, ROS are not only detrimental to cells and tissues but they are also involved in the regulation of many physiological processes including receptor tyrosine kinase signalling. For instance, the mechanism of ROS in cell signalling is based on the ability of ROS to oxidise and thereby reversibly inactivate the active site cysteine of protein tyrosine phosphatases and other enzymes (Fig.2).
To dissect the apparently opposing functions of ROS in cell cycle progression and cell death signalling, our laboratory takes advantage of knockout mouse models for key redox enzymes including cytosolic thioredoxin reductase, mitochondrial thioredoxin reductase and various models for the different forms of glutathione peroxidase 4 (GPx4). These models along with inducible knockout cells are powerful tools to perturb cellular redox homeostasis in cells and tissues in a spatiotemporal manner. Cross-breeding of these mice with models representing human neurodegenerative disease will unravel the role of ROS in redox-regulated cell signalling and neuronal demise.
- Figure 1. Glutathione and GPx4 sense and translate oxidative stress into a distinct cell death signaling pathway. Low glutathione (GSH) levels, as evident in many neurodegenerative diseases, causes impaired GPx4 function and aberrant 12/15-lipoxygenase (12/15-LOX) activity. Lipid hydroperoxides generated by 12/15-LOX may trigger Bid and apoptosis inducing factor (AIF) activation and neurodegeneration.
- Figure 2. A novel pathway describing of how lipid hydroperoxides (LOOH) regulate receptor tyrosine kinase (RTK) signaling. (A) The ability of lipid hydroperoxides (15-HPETE) to oxidize protein tyrosine phosphates (PTPs; e.g. SHP-1) in vitro was compared with hydrogen peroxide (H2O2), the well-established inducer of PTP oxidation. (B) The concept of PTP regulation by NADPH oxidase derived H2O2 is shown on the right. Stimulation of the receptor triggers superoxide anion and H2O2 formation and PTP oxidation. Glutathione peroxidase 1 (GPx1) and peroxiredoxin II (PrxII) control H2O2 levels. Recent data shows that lipid hydroperoxides (15-HPETE) generated by 12/15-LOX or possibly by other lipoxygenase isoforms effectively oxidize and inactivate PTP’s (left). As GPx4 reduces peroxidised lipids, GPx4 may be regarded also as an important regulator of RTK signaling.
Most important publications:
Mannes AM, Seiler A, Bosello V, Maiorino M, Conrad M: The cysteine mutant of mammalian GPx4 rescues cell death induced by disruption of the wild type selenoenzyme. FASEB J. Mar 14. [Epub ahead of print] (2011)
Conrad M, Sandin A, Förster H, Seiler A, Frijhoff J, Dagnell M, Bornkamm GW, Rådmark O, Hooft van Huijsduijnen R, Aspenström P, Böhmer F, Östman A: 12/15-lipoxygenase-derived lipid peroxides control receptor tyrosine kinase signaling through oxidation of protein tyrosine phosphatases. Proc. Natl. Acad. Sci. U S A. 107, 15774-15779 (2010)
Seiler A, Schneider M, Förster H, Roth S, Wirth EK, Culmsee C, Plesnila N, Kremmer E, Rådmark O, Wurst W, Bornkamm GW, Schweizer U, Conrad M: Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent and AIF-mediated cell death. Cell Metab. 8, 237-248 (2008) [Editorial: Loscalzo J. Membrane redox state and apoptosis: death by peroxide Cell Metab. 8:182-183 (2008)]
Jakupoglu C, Przemeck GKH, Schneider M, Moreno SG, Mayr N, Hatzopoulos AK, Hrabé de Angelis M, Wurst W, Bornkamm GW, Brielmeier M, Conrad M. Cytoplasmic thioredoxin reductase is essential for embryogenesis but dispensable for cardiac development. Mol. Cell. Biol. 25, 1980-1988 (2005)
Conrad M, Jakupoglu C, Moreno SG, Lippl S, Banjac A, Schneider M, Beck H, Hatzopoulos AK, Just U, Sinowatz F, et al. Essential role for mitochondrial thioredoxin reductase in hematopoiesis, heart development, and heart function. Mol. Cell. Biol. 24, 9414-9423. (2004)