mRNA for N-Bak, a neuron-specific BH3-only splice isoform of Bak, escapes nonsense-mediated decay and is translationally repressed in the neurons.

Peer reviewe

GDNF-deprived sympathetic neurons die via a novel nonmitochondrial pathway

The mitochondrial death pathway is triggered in cultured sympathetic neurons by deprivation of nerve growth factor (NGF), but the death mechanisms activated by deprivation of other neurotrophic factors are poorly studied. We compared sympathetic neurons deprived of NGF to those deprived of glial cell line–derived neurotrophic factor (GDNF). In contrast to NGF-deprived neurons, GDNF-deprived neurons did not die via the mitochondrial pathway. Indeed, cytochrome c was not released to the cytosol; Bax and caspase-9 and -3 were not involved; overexpressed Bcl-xL did not block the death; and the mitochondrial ultrastructure was not changed. Similarly to NGF-deprived neurons, the death induced by GDNF removal is associated with increased autophagy and requires multiple lineage kinases, c-Jun and caspase-2 and -7. Serine 73 of c-Jun was phosphorylated in both NGF- and GDNF-deprived neurons, whereas serine 63 was phosphorylated only in NGF-deprived neurons. In many NGF-deprived neurons, the ultrastructure of the mitochondria was changed. Thus, a novel nonmitochondrial caspase-dependent death pathway is activated in GDNF-deprived sympathetic neurons

Characterization of the Structural and Functional Determinants of MANF/CDNF in Drosophila In Vivo Model

Peer reviewe

Retarded Growth and Deficits in the Enteric and Parasympathetic Nervous System in Mice Lacking GFRα2, a Functional Neurturin Receptor

AbstractGlial cell line–derived neurotrophic factor (GDNF) and a related protein, neurturin (NTN), require a GPI-linked coreceptor, either GFRα1 or GFRα2, for signaling via the transmembrane Ret tyrosine kinase. We show that mice lacking functional GFRα2 coreceptor (Gfra2−/−) are viable and fertile but have dry eyes and grow poorly after weaning, presumably due to malnutrition. While the sympathetic innervation appeared normal, the parasympathetic cholinergic innervation was almost absent in the lacrimal and salivary glands and severely reduced in the small bowel. Neurite outgrowth and trophic effects of NTN at low concentrations were lacking in Gfra2−/− trigeminal neurons in vitro, whereas responses to GDNF were similar between the genotypes. Thus, GFRα2 is a physiological NTN receptor, essential for the development of specific postganglionic parasympathetic neurons

Antioxidative CXXC Peptide Motif From Mesencephalic Astrocyte-Derived Neurotrophic Factor Antagonizes Programmed Cell Death

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a potent survival-promoting protein with neurorestorative effect for neurodegenerative diseases. Its mechanism of action, albeit poorly known, depends strongly on the CXXC motif (CKGC). Here we studied the survival-promoting properties of the CKGC tetrapeptide from MANF. In the Jurkat T lymphocytic cell line, CKGC potently inhibits death receptor Fas-induced apoptosis and mildly counteracts mitochondrial apoptosis and necroptosis. The peptide with serines instead of cysteines (SKGS) has no survival-promoting activity. The cytoprotective efficiency of the peptide against Fas-induced apoptosis is significantly improved by reduction of its cysteines by dithiotreitol, suggesting that it protects the cells via cysteine thiol groups, partially as an antioxidant. CKGC neutralizes the reactive oxygen species, maintains the mitochondrial membrane potential and prevents activation of the effector caspases in the Jurkat cells with activated Fas. The peptide does not require intracellular administration, as it is endocytosed and resides mainly in the Golgi. Finally, the peptide also potently promotes survival of cultured primary dopaminergic neurons.Peer reviewe

A territorial community as a paradigm?

In this article, the author provides a cursory introduction of the idea to base the interpretation of the functional mechanisms of territorial communities on Kuhn’s treatment of the paradigms of scientific communities. According to the author’s interpretation and treatment, territorial communities are human associations that are related to self-organizing territories, the sequence of timely states, which are being called a process. From this, it ensues that a territorial community is a process. Based on the author’s position and the context of territorial communities, paradigms can be explained as follows: the paradigms of territorial communities determine the important objects with which the community deals and the related problems and/or questions that are established and the methods whereby theses problems and/or questions are resolved