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Mutations in the enzyme superoxide dismutase-1 (SOD1) cause hereditary variants of the fatal motor neuron disease amyotrophic lateral sclerosis (ALS). The pathophysiology of the disease is non-cell-autonomous: neurotoxicity is derived not only from mutant motor neurons but also from mutant neighbouring non-neuronal cells. In particular, microglia contribute to disease progression. By investigating acute lesions of spinal cord white matter in anaesthetised mice with fluorescently labelled microglia and axons using in vivo 2-photon laser-scanning microscopy (2P-LSM), we identified the messenger nitric oxide (NO) as a modulator of activated microglia. Subsequently, we investigated the role of microglia-related neuroinflammation in the affected lateral spinal cord of the ALS-linked transgenic SOD1 G93A mice. Different phases of microglia-mediated inflammation were observed: highly reactive microglial cells in preclinical stages and morphologically transformed ameboid microglia that have lost their function of tissue surveillance and injury-directed response in clinical stages. In another study, we observed rapid morphological reactions of mutant astroglial cells towards laser-induced axonal transection. Finally, we began to investigate the effect of methylene blue as an inhibitor of the NO pathway on microglia-mediated inflammation in affected motor parts of the spinal cord. An understanding of the pathomechanisms of degenerative processes in the spinal cord will be a prerequisite to develop efficient therapies for ALS. © Georg Thieme Verlag KG Stuttgart · New York. Source

Montani L.,Institute Biologia Molecular e Celular | Montani L.,ETH Zurich | Buerki-Thurnherr T.,ETH Zurich | Buerki-Thurnherr T.,Empa - Swiss Federal Laboratories for Materials Science and Technology | And 16 more authors.
Development (Cambridge) | Year: 2014

Myelination allows rapid saltatory propagation of action potentials along the axon and is an essential prerequisite for the normal functioning of the nervous system. During peripheral nervous system (PNS) development, myelin-forming Schwann cells (SCs) generate radial lamellipodia to sort and ensheath axons. This process requires controlled cytoskeletal remodeling, and we show that SC lamellipodia formation depends on the function of profilin 1 (Pfn1), an actinbinding protein involved in microfilament polymerization. Pfn1 is inhibited upon phosphorylation by ROCK, a downstream effector of the integrin linked kinase pathway. Thus, a dramatic reduction of radial lamellipodia formation is observed in SCs lacking integrinlinked kinase or treated with the Rho/ROCK activator lysophosphatidic acid. Knocking down Pfn1 expression by lentiviralmediated shRNA delivery impairs SC lamellipodia formation in vitro, suggesting a direct role for this protein in PNS myelination. Indeed, SC-specific gene ablation of Pfn1 in mice led to profound radial sorting and myelination defects, confirming a central role for this protein in PNS development. Our data identify Pfn1 as a key effector of the integrin linked kinase/Rho/ROCK pathway. This pathway, acting in parallel with integrin β1/LCK/Rac1 and their effectors critically regulates SC lamellipodia formation, radial sorting and myelination during peripheral nervous system maturation. © 2014. Published by The Company of Biologists Ltd. Source

Eckstein F.,Max Planck Institute For Experimentelle Medizin
Nucleic Acid Therapeutics | Year: 2014

Phosphorothioates have found their usefulness in the general area of oligonucleotide therapeutic applications. Initially this modification was introduced into the antisense methodology because of the nuclease resistance of the phosphorothioate linkage in comparison with that of the phosphate linkage. However, as experimental data accumulated, it was detected that this chemical modification also facilitates cellular uptake and bioavailibity in vivo. Thus, today the majority of therapeutic oligonucleotides contain this modification. This review will discuss the historical development of this modification and present some of its chemical properties where they differ from those of the phosphate group. The antisense application will be discussed in the original context with cleavage of the target mRNA, but other target RNAs such as microRNAs and long noncoding RNAs will also be covered. It continues with applications where the target RNA should not be cleaved. A brief presentation of decoy oligonucleotides will be included, as well as some miscellaneous applications. Cellular uptake is a crucial step for oligonucleotides to reach their target and will be briefly reviewed. Lastly, a most surprising recent observation is the presence of phosphorothioate groups in bacterial DNA where functions still remain to be fully determined. © Copyright 2014, Mary Ann Liebert, Inc. 2014. Source

Schizophrenias are diagnosed purely clinically. The biological basis for this clinical entity is still fully unknown. Genetic studies have revealed some interesting hints but have not led to the identification of actual disease genotypes. On the contrary, it has become more and more probable that widely differing genotype constellations together with manifold environmental factors can trigger schizophrenia according to the motto "many roads lead to Rome..o". Thus, new strategies that allow a better insight into complex genotype-phenotype relationships, e. g. PGAS (phenotype-based genetic associations studies) are urgently needed. PGAS became possible on the basis of the GRAS data collection, the as yet largest worldwide phenotypical databank of schizophrenic patients. First PGAS proof-of-concept results on cognition or development-relevant genes are already available. © Georg Thieme Verlag KG Stuttgart, New York. Source

Sussulini A.,University of Campinas | Sussulini A.,Max Planck Institute For Experimentelle Medizin | Sussulini A.,University of Sao Paulo
Advances in Biological Psychiatry | Year: 2014

Bipolar disorder (BD) is a chronic psychiatric illness characterised by transitions between manic and depressive episodes. Diagnosis of BD is based on subjective clinical evaluation and, consequently, quite difficult, due to the oscillating character of the disease. Increasing accuracy regarding BD diagnosis can improve the mental health and treatment of patients. A path that can lead to a more reliable medical diagnostic of BD and also possibly to an optimisation of treatment for each patient is the identification of specific biological markers. Recently, proteomics and metabolomics have become the most applied advanced analytical tools allowing the discovery of protein and metabolite biomarkers for diseases and/or treatments. The present chapter reviews studies described in the literature that employ proteomic and metabolomic strategies to investigate potential biomarkers for BD and also for lithium therapy, which is the most widely used drug treatment of this illness. The main results from investigations using human samples are presented, as well as hypotheses concerning the biological processes and molecular mechanisms involved in BD pathophysiology and treatment, as demonstrated by proteomic and metabolomic analyses. © 2014 S. Karger AG, Basel. Source

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