We have previously shown that two tumor necrosis factor (TNF) receptors (TNFR) exhibit antagonistic functions during neurodegenerative processes in vivo with TNFR1 aggravating and TNFR2 reducing neuronal cell loss, respectively. To elucidate the neuroprotective signaling pathways of TNFR2, we investigated glutamate-induced excitotoxicity in primary cortical neurons. TNF-expressing neurons from TNF-transgenic mice were found to be strongly protected from glutamate-induced apoptosis. Neurons from wild type and TNFR1^-/- mice prestimulated with TNF or agonistic TNFR2-specific antibodies were also resistant to excitotoxicity, whereas TNFR2^-/- neurons died upon glutamate and/or TNF exposures. Both protein kinase B/Akt and nuclear factor-κB (NF-κB) activation were apparent upon TNF treatment. Both TNFR1 and TNFR2 induced the NF-κB pathway, yet with distinguishable kinetics and upstream activating components, TNFR1 only induced transient NF-κB activation, whereas TNFR2 facilitated long term phosphatidylinositol 3-kinase-dependent NF-κB activation strictly. Glutamate-induced triggering of the ionotropic N-methyl-d-aspartate receptor was required for the enhanced and persistent phosphatidylinositol 3-kinase-dependent NF-κB activation by TNFR2, indicating a positive cooperation of TNF and neurotransmitter-induced signal pathways. TNFR2-induced persistent NF-κB activity was essential for neuronal survival. Thus, the duration of NF-κB activation is a critical determinant for sensitivity toward excitotoxic stress and is dependent on a differential upstream signal pathway usage of the two TNFRs.

It has been widely accepted that neurogenesis continues throughout life. Neural stem cells can be found in the ventricular zone of the embryonic and in restricted regions of the adult central nervous system, including subventricular and subgranular zones of the hippocampal dentate gyrus. The network of signaling mechanisms determining whether neural stem cells remain in a proliferative state or differentiate is only partly discovered. Recent advances indicate that glutamate (Glu), the predominant excitatory neurotransmitter in mature neurons, can influence immature neural cell proliferation and differentiation, as well. Despite many similarities, Glu actions on neurogenesis in the developing and adult brain show distinct differences and are far from being clear. Due to alterations of Glu transport mechanisms, extracellular Glu level is high in the embryonic CNS. Glu acts non-synaptically on dividing progenitors either by directly activating ionotropic and/or metabotropic Glu receptors or can influence other cells which are located in the vicinity of proliferating cells and produce molecules regulating neural precursor cell proliferation by other mechanisms. Due to the complexity of signaling pathways and to regional differences in neural precursors, Glu can influence proliferation and neuronal commitment as well, and acts as a positive regulator of neurogenesis. Brain injuries like ischemia, epilepsy or stress lead to severe neuronal death and additionally, influence neurogenesis, as well. Glu homeostasis is altered under these pathological circumstances, implying that therapeutic treatments mediating Glu signaling might be useful to increase neuronal replacement after cell loss in the brain.

In vitro velocities of several cell types have been measured using computer controlled video microscopy, which allowed the recording of the cells' trajectories over several days. On the basis of our large data sets we show that the locomotion activity displays a universal exponential distribution. Thus, motion resulting from complex cellular processes can be well described by an unexpected, but very simple, distribution function. A simple phenomenological model based on the interaction of various cellular processes and finite ATP production rate is proposed to explain these experimental results.

Autophagy functions as a main route for the degradation of superfluous and damaged constituents of the cytoplasm. Defects in autophagy are implicated in the development of various age-dependent degenerative disorders such as cancer, neurodegeneration and tissue atrophy, and in accelerated aging. To promote basal levels of the process in pathological settings, we previously screened a small molecule library for novel autophagy-enhancing factors that inhibit the myotubularin-related phosphatase MTMR14/Jumpy, a negative regulator of autophagic membrane formation. Here we identify AUTEN-99 (autophagy enhancer-99), which activates autophagy in cell cultures and animal models. AUTEN-99 appears to effectively penetrate through the blood-brain barrier, and impedes the progression of neurodegenerative symptoms in Drosophila models of Parkinson’s and Huntington’s diseases. Furthermore, the molecule increases the survival of isolated neurons under normal and oxidative stress-induced conditions. Thus, AUTEN-99 serves as a potent neuroprotective drug candidate for preventing and treating diverse neurodegenerative pathologies, and may promote healthy aging.

Autophagy is a major molecular mechanism that eliminates cellular damage in eukaryotic organisms. Basal levels of autophagy are required for maintaining cellular homeostasis and functioning. Defects in the autophagic process are implicated in the development of various age-dependent pathologies including cancer and neurodegenerative diseases, as well as in accelerated aging. Genetic activation of autophagy has been shown to retard the accumulation of damaged cytoplasmic constituents, delay the incidence of age-dependent diseases, and extend life span in genetic models. This implies that autophagy serves as a therapeutic target in treating such pathologies. Although several autophagy-inducing chemical agents have been identified, the majority of them operate upstream of the core autophagic process, thereby exerting undesired side effects. Here, we screened a small-molecule library for specific inhibitors of MTMR14, a myotubularin-related phosphatase antagonizing the formation of autophagic membrane structures, and isolated AUTEN-67 (autophagy enhancer-67) that significantly increases autophagic flux in cell lines and in vivo models. AUTEN-67 promotes longevity and protects neurons from undergoing stress-induced cell death. It also restores nesting behavior in a murine model of Alzheimer disease, without apparent side effects. Thus, AUTEN-67 is a potent drug candidate for treating autophagy-related diseases.