Nitric Oxide Mediated Signal Transduction in Networks of Human ...

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diseases including Alzheimers, Amyotrophic lateral sclerosis (ALS) and Parkinson diseases (Madhusoodanan and Murad, 2007). The role of NO in the development of Parkinson disease has been extensively studied in 1-methyl- 4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) induced animal models. Previous studies implicated that mice lacking nNOS are more resistant to MPTP induced neurotoxicity (Przedborski et al., 1996; Matthews et al., 1997). The nNOS inhibitor 7NI has been shown to protect against MPTP-induced neurotoxicity in experimental animals (Kurosaki et al., 2002; Watanabe et al., 2008). 7NI has been also showed to protect from 6-OHDA induced neurodegeneration whereas NO donor worsened the neurodegeneration (Di Matteo et al., 2009). The majority of studies indicated cGMP independent mechanism of action of NO in mediating MPTP induced neurotoxicity. These cGMP-independent actions of NO include oxidation of thiols, S-nitrosylation and nitration of proteins (Madhusoodanan and Murad, 2007). In Alzheimer’s disease (AD) all the three isoforms of NOS have been shown to be elevated, indicating an important role for NO in the pathomechanism of AD (Thorns et al., 1998; Lüth 2001). Nitrotyrosine which has been found in AD patients was highly co-localized with nNOS in cortical pyramidal cells (Simic et al., 2000; Sultana et al., 2006). Immunocytochemical methods demonstrated that the nNOS, iNOS and nitrotyrosine immunopositive cell bodies over the entire chronic AD patients brains (Fernández-Vizarra et al., 2004). Since the expression and activity of nNOS is increased in many CNS diseases, the NO/cGMP signaling pathway could be a putative target for developing drugs. In line with this, several nNOS inhibitors were developed but appear to have side effects (Zhou and Zhu, 2009). To minimize unwanted effects in recent years more attention is given toward designing a selective nNOS inhibitor with a potential implication to target neurodegenerative diseases (Silverman, 2009). On the other hand NO synthesized by eNOS has been shown to be neuroprotective in an in vitro model of ALS (De Palma et al., 2008). Here, overexpression of eNOS by neurons has been suggested as a neuroprotective mechanism in neurodegenerative diseases. Changes in histone acetylation that certainly involve NO signaling have been implicated to partially improve memory loss and neurodegeneration (Fischer et al., 2007, Riccio et al., 2006, Nott et al., 2008). Thus, careful manipulation of NO signaling may prove to be a potential therapeutic approach in neurodegenerative disorders. 1.5. Human neuronal stem cells as a model of developing nerve cells Stem cells are defined as precursor cells that have the ability to self-renew and to generate various differentiating cell types. Pluripotent stem cells can give rise theoretically to every cell type in the animal body including neurons. Three types of mammalian pluripotent stem cell lines have been 9
isolated: embryonal carcinoma (EC) cells, the stem cells of testicular tumours; embryonic stem (ES) cells derived from pre-implantation embryos; and embryonic germ (EG) cells derived from primordial germ cells (PGCs) of the post-implantation embryo (Donovan and Gearhart, 2001). Neuronal stem cells (NSC) are pluripotent cells that have the ability to generate the three major cell types of the CNS; neurons, astrocytes and oligodendrocytes. The search for a therapeutic option to treat neurodegenerative diseases caused an expansion of NSC biology, which revealed numerous transcription factors, growth factors and signaling pathways involved in development and regeneration of CNS (Gage, 2000; Curtis et al., 2003; Jin et al., 2004; Shan et al., 2006; Boucherie and Hermans, 2009). Neuronal stem cells could be employed as important tool to dissect the development of human nervous system. For example, several of the existing human EC stem cell lines provide robust and simple culture systems to study certain aspects of cellular differentiation that mimic vertebrate neurogenesis (Przyborski et al., 2004). The teratocarcinoma cell line Ntera2 (NT2) which is derived from a human testicular cancer can be induced to differentiate into fully functional postmitotic neurons and other cell types of the neuronal lineages (Andrews 1984; Pleasure et al., 1992; Paquet-Durand and Bicker, 2007). NT2 cells shares many similarity with human embryonic stem cells (Schwartz et al., 2005) and differentiation of NT2 cells into neurons has been suggested to resemble vertebrate neurogenesis (Przyborski et al., 2000; Houldsworth et al., 2002; Przyborski et al. 2003). Moreover, fully differentiated NT2 neurons have been shown to express a variety of neurotransmitters in vitro (Guillemain et al., 2000; Podrygajlo et al., 2009) and form functional synapse (Hartley et al., 1998; Podrygajlo et al., 2010). More restricted stem cells with developmental potential can also be obtained from a variety of tissues at different stages of development, including mature tissues from adult and fetal organisms. For example, fetal human neural progenitor cells (hNPCs) that have the capacity to give neurons, astrocytes and oligodendrocytes have been shown to mimic early developing human brain with respect to cell proliferation, migration and differentiation (Fritsche et al., 2005; Moors et al., 2007; Moors et al., 2009). NSCs also exist within limited regions of the adult CNS (SVZ and hippocampus), and it is possible to isolate and expand these cells to give rise to progenitor cells restricted to defined neural lineages, neuronal and glial cells (Gage, 2000). Another promising model for developing human neurons is induced pluripotent stem cells (iPS) obtained by molecular reprogramming of somatic cells. These cells have been successfully differentiated into dopaminergic neurons and functionally integrated into rat brain (Werning et al., 2008). 10
Page 1: Fehlerhafte Abgabe! Original Artike
Page 4 and 5: Supervisor: Prof. Dr. Gerd Bicker D
Page 6 and 7: Publications: Tegenge, M. A., and B
Page 8 and 9: List of abbreviations AD, Alzheimer
Page 10 and 11: 1. Introduction 1.1. Nitric oxide s
Page 12 and 13: several proteins that is responsibl
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Page 20 and 21: 1.6. Hypothesis and aim of the stud
Page 22 and 23: al., 2004; 2006), I tested the effe
Page 24 and 25: ecto abs). Upon fusion of synaptic
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Page 30 and 31: disturb differentiation of normal h
Page 32 and 33: 23-35. Knipp, S., and Bicker, G. (2
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Page 36 and 37: Silverman, R. B. (2009). Design of
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Page 40 and 41: Summary The complex mammalian centr
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1444 | M. A. Tegenge et al. subsequ
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1446 | M. A. Tegenge et al. Micheva
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Abstract Neuronal migration is a ce
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(8-Bromoguanosine-3’, 5’-cyclop
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Fig. 1 The antibody against nNOS re
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Fig. 3 Immunocytochemical character
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Fig. 5 NO donor and cell membrane p
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NO/cGMP/PKG signaling mediate the m
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Bredt, D. S. and Snyder, S. H. (199
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Declaration I herewith declare that
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