Molecular mechanism of neurodegeneration in Molybdenum cofactor deficiency:
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| Format: | Abschlussarbeit Buch |
| Sprache: | English |
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Köln
2016
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| Beschreibung: | viii, 103 Seiten Illustrationen 21 cm |
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| 245 | 1 | 0 | |a Molecular mechanism of neurodegeneration in Molybdenum cofactor deficiency |c vorgelegt von Avadh Kumar |
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| adam_text | TABLE OF CONTENTS
LIST OF
FIGURES....................................................................................................................................................I
LIST OF
TABLES....................................................................................................................................................II
LIST OF
ABBREVIATIONS......................................................................................................................................
ILL
ABSTRACT............................................................................................................................................................VI
ZUSAMMENFASSUNG.......................................................................................................................................VII
1
INTRODUCTION................................................................................................................................................
1
PART A MOLYBDENUM IN HUMAN HEALTH AND NEUROLOGICAL
DISEASES.................................................1
1.1 MOLYBDENUM AND TUNGSTEN IN BIOLOGICAL SYSTEM
S...................................................................1
1.2 MOLYBDENUM COFACTOR AND ITS BIOSYNTHESIS IN HUMANS
...........................................................
1
1.3 HUMAN
MO-ENZYMES.......................................................................................................................4
1.4 MOLYBDENUM COFACTOR AND ISOLATED SO
DEFICIENCY..................................................................
6
1.4.1 GENETICS OF MOCD AND S O D
.................................................................................................6
1.4.2 CLINICAL PRESENTATION IN MOCD AND S O D
............................................................................7
1.4.3 BIOCHEMICAL CHARACTERIZATION OF MOCD AND S O D
............................................................
8
1.4.4 CURRENT STATE OF TREATMENT OPTIONS FOR MOCD AND S O D
................................................10
1.5 TUNGSTATE AS AN INDUCER OF
MOCD.............................................................................................
11
PART B GLUTAMATE RECEPTORS IN NEURODEGENERATION AND NEUROLOGICAL
DISORDERS
........................
12
1.6 GLUTAMATE RECEPTORS AND THEIR
FUNCTIONS...................................................................................13
1.6.1 NMDA
RECEPTORS....................................................................................................................14
1.6.2 AMPA
RECEPTORS.....................................................................................................................14
1.7 NMDARS IN EXCITOTOXICITY AND NEUROLOGICAL
DISORDERS...........................................................15
1.8 NMDAR ACTIVATION AND CA2+ DEREGULATION IN NEURONAL
DEATH..............................................16
1.9 CALPAINS IN NEURODEGENERATION AND NEUROLOGICAL DISEASES
.................................................
17
1.10 NMDAR ANTAGONISTS IN NEUROPROTECTION
1.11 CELL DEATH PATHWAYS IN EXCITOTOXIC NEURONAL AND BRAIN DAM AG
E........................................19
1.11.1
APOPTOSIS.................................................................................................................................20
1.11.2
NECROSIS...................................................................................................................................
23
1.11.3
FERROPTOSIS..............................................................................................................................
23
1.12 AIMS OF
WORK...................................................................................................................................
24
2
RESULTS.........................................................................................................................................................1
2.1 CYSTEINE METABOLISM DEREGULATION IN M OC D /S O D
...................................................................
1
2.1.1 NEUROTOXIC CHARACTERIZATION OF MOCD-RELATED CYSTEINE METABOLITES
............................
1
2.1.2 GLUTAMATE RECEPTOR-MEDIATED TOXICITY OF CYSTEINE
METABOLITES.....................................2
2.1.3 EFFECT OF LOW SSC CONCENTRATIONS ON NEURONAL VIABILITY
..................................................
3
2.1.4 SULFITE TOXICITY IS INDIRECTLY RELATED TO GLUTAMATE
RECEPTORS............................................5
2.1.5 SSC EXHIBITS TOXICITY ONLY IN NEURONAL
CELLS......................................................................
6
2.1.6 MEMANTINE PREVENTS SSC-MEDIATED EXCITOTOXICITY IN PRIMARY NEURONS
.....................
8
2.2 NMDAR ACTIVATION AND CA2+-DEPENDENT DOWNSTREAM EVENTS IN
SSC-MEDIATED
NEUROTOXICITY...................................................................................................................................................9
2.2.1 SSC ACTIVATES CA2*-DEPENDENT CALPAIN-1 IN PRIMARY
NEURONS....................................10
2.2.2 CALPAIN-1 TRIGGERS CLEAVAGE OF THE POSTSYNAPTIC PROTEIN GEPHYRIN
AT INHIBITORY
SYNAPSES IN SSC-TREATED
NEURONS......................................................................................................11
2.2.3 INVESTIGATION OF SSC-INDUCED NEUNTE DEGENERATION
......................................................
13
2.3 CELL DEATH MECHANISMS ACTIVATED BY SSC IN PRIMARY NEURONS
..........................................
22
2.4 INDUCTION OF MOCD IN MICE BY ORAL TUNGSTATE
ADMINISTRATION...............................................34
2.4.1 BIOCHEMICAL CHARACTERIZATION OF TUNGSTATE-TREATED M ICE
.............................................
35
2.4.2 HISTOLOGICAL CHARACTERIZATION OF MOCD INDUCED BY TUNGSTATE
.....................................
40
2.4.3 GEPHYRIN IS DEGRADED IN MOCD MICE BRAIN
.....................................................................
42
2.4.4 PREVENTION OF SSC TOXICITY AND TUNGSTATE-INDUCED MOCD BY MEMANTINE
................
43
3
DISCUSSION...............................................................................................................................................46
3.1 IN VITRO CHARACTERIZATION OF MOCD/SOD-ASSOCIATED NEURODEGENERATION
............................
46
3.2 SSC-INDUCED NEUNTE DEGENERATION AND CELL DEATH IN PRIMARY NEURONS
.............................
53
3.2.1 ROLE OF SSC IN NEUNTE
DEGENERATION..................................................................................S3
3.2.2 CASPASE-DEPENDENT CELL DEATH IN SSC TREATED
NEURONS..............................................55
3.2.3 CASPASE-INDEPENDENT CELL DEATH IN SSC TREATED NEURONS
..........................................
57
3.3 IN VIVO CHARACTERIZATION OF THE TUNGSTEN-INDUCED MICE MODEL OF
MOLYBDENUM COFACTOR
DEFICIENCY AND THERAPEUTIC
IMPLICATIONS................................................................................................61
4 MATERIALS AND
METHODS.........................................................................................................................66
4.1
MATERIALS..........................................................................................................................................66
4.1.1 CHEMICALS AND
REAGENTS.....................................................................................................
66
4.1.2 CASPASE AND CALPAIN SUBSTRATES
........................................................................................
66
4.1.3 GLUTAMATE RECEPTORS
BLOCKERS............................................................................................66
4.1.4 TRANSFECTION
REAGENTS..........................................................................................................66
4.1.5 PRIMARY
ANTIBODIES.................................................................................................................
67
4.1.6 SECONDARY
ANTIBODIES...........................................................................................................
67
4.1.7 INSTRUMENTS
......
.
.....................................................................................................................
67
4.1.8 CULTURE MEDIA, ANTIBIOTICS AND AGAR
PLATES.......................................................................68
4.1.9 CULTURE MEDIA FOR
BACTERIA....................................................................................................
68
4.1.10 CULTURE MEDIA FOR EUKARYOTIC
CELLS.....................................................................................68
4.1.11
ANTIBIOTICS...............................................................................................................................
69
4.2 BIOLOGICAL
MATERIAL...........................................................................................................................69
4.2.1 BACTERIAL STRAINS AND
VECTORS................................................................................................69
4.2.2 MOUSE
STRAINS........................................................................................................................
70
4.2.3 MAMMALIAN CELL
LINES............................................................................................................
70
4.3
METHODS...........................................................................................................................................
71
4.3.1 BIOCHEMICAL
METHODS...........................................................................................................
71
4.3.2 MOLECULAR BIOLOGICAL
METHODS.............................................................................................76
4.3.3 CELL BIOLOGICAL
METHODS.......................................................................................................
77
4.3.4 HISTOLOGICAL
TECHNIQUES.........................................................................................................
81
4.4 ANIMAL EXPERIMENTS AND
TREATMENTS.........................................................................................
82
4.4.1 TUNGSTATE TREATMENT OF M IC E
................................................................................................82
4.4.2 INTRAPERITONEAL MEMANTINE INJECTIONS IN
MICE..................................................................82
4.4.3 ROTAROD PERFORMANCE TE S
T...................................................................................................
82
4.4.4
CLASPING...................................................................................................................................
83
4.4.5 STATISTICAL
ANALYSES...............................................................................................................83
5
REFERENCES..............................................................................................................................................84
6
ACKNOWLEDGEMENT..................................................................................................................................99
7 CURRICULUM V ITA E
..................................................................................................................................
100
|
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| spelling | Kumar, Avadh 1984- Verfasser (DE-588)1135991162 aut Molecular mechanism of neurodegeneration in Molybdenum cofactor deficiency vorgelegt von Avadh Kumar Köln 2016 viii, 103 Seiten Illustrationen 21 cm txt rdacontent n rdamedia nc rdacarrier Dissertation Universität zu Köln 2016 (DE-588)4113937-9 Hochschulschrift gnd-content B:DE-101 application/pdf http://d-nb.info/1137189231/04 Inhaltsverzeichnis DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=030681782&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
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| subject_GND | (DE-588)4113937-9 |
| title | Molecular mechanism of neurodegeneration in Molybdenum cofactor deficiency |
| title_auth | Molecular mechanism of neurodegeneration in Molybdenum cofactor deficiency |
| title_exact_search | Molecular mechanism of neurodegeneration in Molybdenum cofactor deficiency |
| title_full | Molecular mechanism of neurodegeneration in Molybdenum cofactor deficiency vorgelegt von Avadh Kumar |
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| title_short | Molecular mechanism of neurodegeneration in Molybdenum cofactor deficiency |
| title_sort | molecular mechanism of neurodegeneration in molybdenum cofactor deficiency |
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