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Creatine Protects against Excitoxicity in an In Vitro Model of Neurodegeneration
Just Genius, Johanna Geiger, Andreas Bender, Hans-Jürgen M?ller, Thomas Klopstock, Dan Rujescu
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0030554
Abstract: Creatine has been shown to be neuroprotective in aging, neurodegenerative conditions and brain injury. As a common molecular background, oxidative stress and disturbed cellular energy homeostasis are key aspects in these conditions. Moreover, in a recent report we could demonstrate a life-enhancing and health-promoting potential of creatine in rodents, mainly due to its neuroprotective action. In order to investigate the underlying pharmacology mediating these mainly neuroprotective properties of creatine, cultured primary embryonal hippocampal and cortical cells were challenged with glutamate or H2O2. In good agreement with our in vivo data, creatine mediated a direct effect on the bioenergetic balance, leading to an enhanced cellular energy charge, thereby acting as a neuroprotectant. Moreover, creatine effectively antagonized the H2O2-induced ATP depletion and the excitotoxic response towards glutamate, while not directly acting as an antioxidant. Additionally, creatine mediated a direct inhibitory action on the NMDA receptor-mediated calcium response, which initiates the excitotoxic cascade. Even excessive concentrations of creatine had no neurotoxic effects, so that high-dose creatine supplementation as a health-promoting agent in specific pathological situations or as a primary prophylactic compound in risk populations seems feasible. In conclusion, we were able to demonstrate that the protective potential of creatine was primarily mediated by its impact on cellular energy metabolism and NMDA receptor function, along with reduced glutamate spillover, oxidative stress and subsequent excitotoxicity.
Mapping Gene Associations in Human Mitochondria using Clinical Disease Phenotypes
Curt Scharfe ,Henry Horng-Shing Lu,Jutta K. Neuenburg,Edward A. Allen,Guan-Cheng Li,Thomas Klopstock,Tina M. Cowan,Gregory M. Enns,Ronald W. Davis
PLOS Computational Biology , 2009, DOI: 10.1371/journal.pcbi.1000374
Abstract: Nuclear genes encode most mitochondrial proteins, and their mutations cause diverse and debilitating clinical disorders. To date, 1,200 of these mitochondrial genes have been recorded, while no standardized catalog exists of the associated clinical phenotypes. Such a catalog would be useful to develop methods to analyze human phenotypic data, to determine genotype-phenotype relations among many genes and diseases, and to support the clinical diagnosis of mitochondrial disorders. Here we establish a clinical phenotype catalog of 174 mitochondrial disease genes and study associations of diseases and genes. Phenotypic features such as clinical signs and symptoms were manually annotated from full-text medical articles and classified based on the hierarchical MeSH ontology. This classification of phenotypic features of each gene allowed for the comparison of diseases between different genes. In turn, we were then able to measure the phenotypic associations of disease genes for which we calculated a quantitative value that is based on their shared phenotypic features. The results showed that genes sharing more similar phenotypes have a stronger tendency for functional interactions, proving the usefulness of phenotype similarity values in disease gene network analysis. We then constructed a functional network of mitochondrial genes and discovered a higher connectivity for non-disease than for disease genes, and a tendency of disease genes to interact with each other. Utilizing these differences, we propose 168 candidate genes that resemble the characteristic interaction patterns of mitochondrial disease genes. Through their network associations, the candidates are further prioritized for the study of specific disorders such as optic neuropathies and Parkinson disease. Most mitochondrial disease phenotypes involve several clinical categories including neurologic, metabolic, and gastrointestinal disorders, which might indicate the effects of gene defects within the mitochondrial system. The accompanying knowledgebase (http://www.mitophenome.org/) supports the study of clinical diseases and associated genes.
TOM40 Mediates Mitochondrial Dysfunction Induced by α-Synuclein Accumulation in Parkinson’s Disease
Andreas Bender, Paula Desplats, Brian Spencer, Edward Rockenstein, Anthony Adame, Matthias Elstner, Christoph Laub, Sarina Mueller, Andrew O. Koob, Michael Mante, Emily Pham, Thomas Klopstock, Eliezer Masliah
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0062277
Abstract: Alpha-synuclein (α-Syn) accumulation/aggregation and mitochondrial dysfunction play prominent roles in the pathology of Parkinson’s disease. We have previously shown that postmortem human dopaminergic neurons from PD brains accumulate high levels of mitochondrial DNA (mtDNA) deletions. We now addressed the question, whether alterations in a component of the mitochondrial import machinery -TOM40- might contribute to the mitochondrial dysfunction and damage in PD. For this purpose, we studied levels of TOM40, mtDNA deletions, oxidative damage, energy production, and complexes of the respiratory chain in brain homogenates as well as in single neurons, using laser-capture-microdissection in transgenic mice overexpressing human wildtype α-Syn. Additionally, we used lentivirus-mediated stereotactic delivery of a component of this import machinery into mouse brain as a novel therapeutic strategy. We report here that TOM40 is significantly reduced in the brain of PD patients and in α-Syn transgenic mice. TOM40 deficits were associated with increased mtDNA deletions and oxidative DNA damage, and with decreased energy production and altered levels of complex I proteins in α-Syn transgenic mice. Lentiviral-mediated overexpression of Tom40 in α-Syn-transgenic mice brains ameliorated energy deficits as well as oxidative burden. Our results suggest that alterations in the mitochondrial protein transport machinery might contribute to mitochondrial impairment in α-Synucleinopathies.
Neuromelanin, neurotransmitter status and brainstem location determine the differential vulnerability of catecholaminergic neurons to mitochondrial DNA deletions
Matthias Elstner, Sarina K Müller, Lars Leidolt, Christoph Laub, Lena Krieg, Falk Schlaudraff, Birgit Liss, Chris Morris, Douglass M Turnbull, Eliezer Masliah, Holger Prokisch, Thomas Klopstock, Andreas Bender
Molecular Brain , 2011, DOI: 10.1186/1756-6606-4-43
Abstract: In healthy aged individuals, ΔmtDNA levels were highest in pigmented catecholaminergic neurons (25.2 ± 14.9%), followed by non-pigmented catecholamergic (18.0 ± 11.2%) and non-catecholaminergic neurons (12.3 ± 12.3%; p < 0.001). Within the catecholaminergic population, ΔmtDNA levels were highest in dopaminergic neurons of the SNc (33.9 ± 21.6%) followed by dopaminergic neurons of the VTA (21.9 ± 12.3%) and noradrenergic neurons of the LC (11.1 ± 11.4%; p < 0.001). In PD patients, there was a trend to an elevated mutation load in surviving non-pigmented nigral neurons (27.13 ± 16.73) compared to age-matched controls (19.15 ± 11.06; p = 0.052), but levels where similar in pigmented nigral neurons of PD patients (41.62 ± 19.61) and controls (41.80 ± 22.62).Catecholaminergic brainstem neurons are differentially susceptible to mtDNA damage. Pigmented dopaminergic neurons of the SNc show the highest ΔmtDNA levels, possibly explaining the exceptional vulnerability of the nigro-striatal system in PD and aging. Although loss of pigmented noradrenergic LC neurons also is an early feature of PD pathology, mtDNA levels are not elevated in this nucleus in healthy controls. Thus, ΔmtDNA are neither an inevitable consequence of catecholamine metabolism nor a universal explanation for the regional vulnerability seen in PD.Oxidative stress and mitochondrial dysfunction are believed to have a dominant role in mechanisms of aging and neurodegenerative disorders such as Parkinson disease (PD) [1]. The mitochondrial theory of aging proposes that production of reactive oxygen species (ROS) in mitochondria causes accumulating damage to proteins, lipids, and mitochondrial DNA (mtDNA). As a consequence, mitochondrial dysfunction and ROS production may build up in a vicious cycle that eventually results in cell death [2,3]. Damage to mtDNA is central to this theory and early studies provide evidence for the accumulation of somatic mtDNA deletions (ΔmtDNA) in aging postmitotic tissues with hi
Pleiotropic effects in Eya3 knockout mice
Torben S?ker, Claudia Dalke, Oliver Puk, Thomas Floss, Lore Becker, Ines Bolle, Jack Favor, Wolfgang Hans, Sabine M H?lter, Marion Horsch, Magdalena Kallnik, Eva Kling, Corinna Moerth, Anja Schrewe, Christian Stigloher, Stefanie Topp, Valerie Gailus-Durner, Beatrix Naton, Johannes Beckers, Helmut Fuchs, Boris Ivandic, Thomas Klopstock, Holger Schulz, Eckhard Wolf, Wolfgang Wurst, Laure Bally-Cuif, Martin de Angelis, Jochen Graw
BMC Developmental Biology , 2008, DOI: 10.1186/1471-213x-8-118
Abstract: Expression analysis of Eya3 by in-situ hybridizations and β-Gal-staining of Eya3 mutant mice revealed abundant expression of the gene throughout development, e.g. in brain, eyes, heart, somites and limbs suggesting pleiotropic effects of the mutated gene. A similar complex expression pattern was observed also in zebrafish embryos.The phenotype of young adult Eya3 mouse mutants was systematically analyzed within the German Mouse Clinic. There was no obvious defect in the eyes, ears and kidneys of Eya3 mutant mice. Homozygous mutants displayed decreased bone mineral content and shorter body length. In the lung, the tidal volume at rest was decreased, and electrocardiography showed increased JT- and PQ intervals as well as decreased QRS amplitude. Behavioral analysis of the mutants demonstrated a mild increase in exploratory behavior, but decreased locomotor activity and reduced muscle strength. Analysis of differential gene expression revealed 110 regulated genes in heart and brain. Using real-time PCR, we confirmed Nup155 being down regulated in both organs.The loss of Eya3 in the mouse has no apparent effect on eye development. The wide-spread expression of Eya3 in mouse and zebrafish embryos is in contrast to the restricted expression pattern in Xenopus embryos. The loss of Eya3 in mice leads to a broad spectrum of minor physiological changes. Among them, the mutant mice move less than the wild-type mice and, together with the effects on respiratory, muscle and heart function, the mutation might lead to more severe effects when the mice become older. Therefore, future investigations of Eya3 function should focus on aging mice.Eya3 is one of four mammalian orthologous genes (Eya1-4) of eyes absent (eya) in Drosophila melanogaster [1,2]. Previous investigations demonstrated that a homozygous knockout of eya function in D. melanogaster results in severe embryonic defects and absence of compound eyes due to eye progenitor cell death [3,4]. Like eyes absent in Drosophil
Dll1 Haploinsufficiency in Adult Mice Leads to a Complex Phenotype Affecting Metabolic and Immunological Processes
Isabel Rubio-Aliaga, Gerhard K. H. Przemeck, Helmut Fuchs, Valérie Gailus-Durner, Thure Adler, Wolfgang Hans, Marion Horsch, Birgit Rathkolb, Jan Rozman, Anja Schrewe, Sibylle Wagner, Sabine M. Hoelter, Lore Becker, Thomas Klopstock, Wolfgang Wurst, Eckhard Wolf, Martin Klingenspor, Boris T. Ivandic, Dirk H. Busch, Johannes Beckers, Martin Hrabé de Angelis
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006054
Abstract: Background The Notch signaling pathway is an evolutionary conserved signal transduction pathway involved in embryonic patterning and regulation of cell fates during development and self-renewal. Recent studies have demonstrated that this pathway is integral to a complex system of interactions, involving as well other signal transduction pathways, and implicated in distinct human diseases. Delta-like 1 (Dll1) is one of the known ligands of the Notch receptors. The role of the Notch ligands is less well understood. Loss-of-function of Dll1 leads to embryonic lethality, but reduction of Delta-like 1 protein levels has not been studied in adult stage. Methodology/Principal Findings Here we present the haploinsufficient phenotype of Dll1 and a missense mutant Dll1 allele (Dll1C413Y). Haploinsufficiency leads to a complex phenotype with several biological processes altered. These alterations reveal the importance of Dll1 mainly in metabolism, energy balance and in immunology. The animals are smaller, lighter, with altered fat to lean ratio and have increased blood pressure and a slight bradycardia. The animals have reduced cholesterol and triglyceride levels in blood. At the immunological level a subtle phenotype is observed due to the effect and fine-tuning of the signaling network at the different levels of differentiation, proliferation and function of lymphocytes. Moreover, the importance of the proteolytic regulation of the Notch signaling network emphasized. Conclusions/Significance In conclusion, slight alterations in one player of Notch signaling alter the entire organism, emphasizing the fine-tuning character of this pathway in a high number of processes.
Standardized, Systemic Phenotypic Analysis of UmodC93F and UmodA227T Mutant Mice
Elisabeth Kemter, Petra Prückl, Birgit Rathkolb, Kateryna Micklich, Thure Adler, Lore Becker, Johannes Beckers, Dirk H. Busch, Alexander A. G?tz, Wolfgang Hans, Marion Horsch, Boris Ivandic, Martin Klingenspor, Thomas Klopstock, Jan Rozman, Anja Schrewe, Holger Schulz, Helmut Fuchs, Valérie Gailus-Durner, Martin Hrabé de Angelis, Eckhard Wolf, Bernhard Aigner
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0078337
Abstract: Uromodulin-associated kidney disease (UAKD) summarizes different clinical features of an autosomal dominant heritable disease syndrome in humans with a proven uromodulin (UMOD) mutation involved. It is often characterized by hyperuricemia, gout, alteration of urine concentrating ability, as well as a variable rate of disease progression inconstantly leading to renal failure and histological alterations of the kidneys. We recently established the two Umod mutant mouse lines UmodC93F and UmodA227T on the C3H inbred genetic background both showing kidney defects analogous to those found in human UAKD patients. In addition, disease symptoms were revealed that were not yet described in other published mouse models of UAKD. To examine if further organ systems and/or metabolic pathways are affected by Umod mutations as primary or secondary effects, we describe a standardized, systemic phenotypic analysis of the two mutant mouse lines UmodA227T and UmodC93F in the German Mouse Clinic. Different genotypes as well as different ages were tested. Beside the already published changes in body weight, body composition and bone metabolism, the influence of the Umod mutation on energy metabolism was confirmed. Hematological analysis revealed a moderate microcytic and erythropenic anemia in older Umod mutant mice. Data of the other analyses in 7-10 month-old mutant mice showed single small additional effects.
Abnormal Brain Iron Metabolism in Irp2 Deficient Mice Is Associated with Mild Neurological and Behavioral Impairments
Kimberly B. Zumbrennen-Bullough, Lore Becker, Lillian Garrett, Sabine M. H?lter, Julia Calzada-Wack, Ilona Mossbrugger, Leticia Quintanilla-Fend, Ildiko Racz, Birgit Rathkolb, Thomas Klopstock, Wolfgang Wurst, Andreas Zimmer, Eckhard Wolf, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabě de Angelis, Steven J. Romney, Elizabeth A. Leibold
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0098072
Abstract: Iron Regulatory Protein 2 (Irp2, Ireb2) is a central regulator of cellular iron homeostasis in vertebrates. Two global knockout mouse models have been generated to explore the role of Irp2 in regulating iron metabolism. While both mouse models show that loss of Irp2 results in microcytic anemia and altered body iron distribution, discrepant results have drawn into question the role of Irp2 in regulating brain iron metabolism. One model shows that aged Irp2 deficient mice develop adult-onset progressive neurodegeneration that is associated with axonal degeneration and loss of Purkinje cells in the central nervous system. These mice show iron deposition in white matter tracts and oligodendrocyte soma throughout the brain. A contrasting model of global Irp2 deficiency shows no overt or pathological signs of neurodegeneration or brain iron accumulation, and display only mild motor coordination and balance deficits when challenged by specific tests. Explanations for conflicting findings in the severity of the clinical phenotype, brain iron accumulation and neuronal degeneration remain unclear. Here, we describe an additional mouse model of global Irp2 deficiency. Our aged Irp2?/? mice show marked iron deposition in white matter and in oligodendrocytes while iron content is significantly reduced in neurons. Ferritin and transferrin receptor 1 (TfR1, Tfrc), expression are increased and decreased, respectively, in the brain from Irp2?/? mice. These mice show impairments in locomotion, exploration, motor coordination/balance and nociception when assessed by neurological and behavioral tests, but lack overt signs of neurodegenerative disease. Ultrastructural studies of specific brain regions show no evidence of neurodegeneration. Our data suggest that Irp2 deficiency dysregulates brain iron metabolism causing cellular dysfunction that ultimately leads to mild neurological, behavioral and nociceptive impairments.
Neurobeachin, a Regulator of Synaptic Protein Targeting, Is Associated with Body Fat Mass and Feeding Behavior in Mice and Body-Mass Index in Humans
Pawel K. Olszewski,Jan Rozman,Josefin A. Jacobsson,Birgit Rathkolb,Siv Str?mberg,Wolfgang Hans,Anica Klockars,Johan Alsi?,Ulf Risérus,Lore Becker,Sabine M. H?lter,Ralf Elvert,Nicole Ehrhardt,Valérie Gailus-Durner,Helmut Fuchs,Robert Fredriksson,Eckhard Wolf,Thomas Klopstock,Wolfgang Wurst,Allen S. Levine,Claude Marcus,Martin Hrabě de Angelis,Martin Klingenspor,Helgi B. Schi?th ?,Manfred W. Kilimann ?
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002568
Abstract: Neurobeachin (Nbea) regulates neuronal membrane protein trafficking and is required for the development and functioning of central and neuromuscular synapses. In homozygous knockout (KO) mice, Nbea deficiency causes perinatal death. Here, we report that heterozygous KO mice haploinsufficient for Nbea have higher body weight due to increased adipose tissue mass. In several feeding paradigms, heterozygous KO mice consumed more food than wild-type (WT) controls, and this consumption was primarily driven by calories rather than palatability. Expression analysis of feeding-related genes in the hypothalamus and brainstem with real-time PCR showed differential expression of a subset of neuropeptide or neuropeptide receptor mRNAs between WT and Nbea+/? mice in the sated state and in response to food deprivation, but not to feeding reward. In humans, we identified two intronic NBEA single-nucleotide polymorphisms (SNPs) that are significantly associated with body-mass index (BMI) in adult and juvenile cohorts. Overall, data obtained in mice and humans suggest that variation of Nbea abundance or activity critically affects body weight, presumably by influencing the activity of feeding-related neural circuits. Our study emphasizes the importance of neural mechanisms in body weight control and points out NBEA as a potential risk gene in human obesity.
Post-Stroke Inhibition of Induced NADPH Oxidase Type 4 Prevents Oxidative Stress and Neurodegeneration
Christoph Kleinschnitz,Henrike Grund,Kirstin Wingler,Melanie E. Armitage,Emma Jones,Manish Mittal,David Barit,Tobias Schwarz,Christian Geis,Peter Kraft,Konstanze Barthel,Michael K. Schuhmann,Alexander M. Herrmann,Sven G. Meuth,Guido Stoll,Sabine Meurer,Anja Schrewe,Lore Becker,Valérie Gailus-Durner,Helmut Fuchs,Thomas Klopstock,Martin Hrabé de Angelis,Karin Jandeleit-Dahm,Ajay M. Shah,Norbert Weissmann,Harald H. H. W. Schmidt
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1000479
Abstract: Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox4?/?) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox4?/? mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy.
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