Verfügbarkeit: ER mitochondria calcium cycle (ERMCC) dysregulation in motor neurons of ALS mouse model as target for new therapeutic strategies

ER mitochondria calcium cycle (ERMCC) dysregulation in motor neurons of ALS mouse model as target for new therapeutic strategies:

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Bibliographische Detailangaben
1. Verfasser:	Tadić, Vedrana 1985- (VerfasserIn)
Format:	Abschlussarbeit Buch
Sprache:	English
Veröffentlicht:	Jena June 2017
Schlagworte:	Hochschulschrift
Online-Zugang:	Inhaltsverzeichnis Inhaltsverzeichnis
Beschreibung:	VIII, 75, xvii Seiten Illustrationen 29 cm

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adam_text	TABLE OF CONTENTS TABLE OF CONTENTS................................................................................................ I LIST OF ABBREVIATIONS........................................................................................ ILL SUMMARY................................................................................................................... V ZUSAMMENFASSUNG.............................................................................................VII 1 INTRODUCTION................................................................................................1 1.1 ALS PATHOLOGY.................................................................................................. 1 1.2 DIAGNOSIS AND THERAPY.....................................................................................3 1.3 MOTOR NEURON INJURY......................................................................................... 5 1.3.1 INTRACELLULAR CA2+ HOMEOSTASIS AND ORGANELLE DYSFUNCTION IN ALS ....... 5 1.3.2 MITOCHONDRIAL IMPAIRMENT AND OXIDATIVE STRESS .................................... 7 1.3.3 ER STRESS AND DEREGULATION OF SIG1 R AT THE MAMS ............................ 8 1.3.4 DNA DAMAGE IN ALS MOTOR NEURONS ................................................... 9 2 AIMS OF THE STUDY.................................................................................... 10 3 MATERIALS AND METHODS........................................................................ 12 3.1 ANIMALS............................................................................................................12 3.2 PRIMARY MOTOR NEURON-ENRICHED CULTURES....................................................13 3.2.1 PREPARATION OF THE PLATES FOR SEEDING OF MOTOR NEURONS .................... 14 3.2.2 PREPARATION OF THE PRIMARY MOTOR NEURON-ENRICHED CULTURES ............. 14 3.2.3 GENOTYPING OF MICE EMBRYOS.............................................................15 3.3 STAINING AND QUANTIFICATION PROTOCOLS.........................................................15 3.3.1 STAINING AND VISUALIZATION OF MITOCHONDRIAL NETWORK ......................... 15 3.3.2 IMMUNOCYTOCHEMISTRY IN PRIMARY MOTOR NEURONS AND ASTROCYTES ...... 17 3.3.3 QUANTIFICATION OF IMMUNOCYTOCHEMISTRY SIGNAL................................. . 17 3.3.4 SURVIVAL ASSAY FOLLOWING PHARMACOLOGICAL MANIPULATION OF ERMCC. 18 3.3.5 INVESTIGATION OF MRNA LEVELS.............................................................19 3.4 CALCIUM IMAGING.............................................................................................19 3.4.1 ANALYSIS OF CALCIUM IMAGING DATA ..................................................... 21 3.5 STATISTICS......................................................................................................... 21 3.6 MEDIA, BUFFERS AND LABORATORY CONSUMABLES .............................................. 23 3.6.1 MEDIA AND SUBSTANCES FOR MOTOR NEURON-ENRICHED CULTURES .............. 23 3.6.2 PRIMERS AND PROGRAMS FOR PCR AND QPCR ....................................... 25 3.6.3 IMMUNOCYTOCHEMISTRY PROTOCOLS FOR MOTOR NEURONS AND ASTROCYTES..26 3.6.4 SUBSTANCES USED FOR CALCIUM IMAGING AND VIABILITY ASSAY ................ 28 3.6.5 SOFTWARE............................................................................................ 28 4 RESULTS........................................................................................................ 29 4.1 G93AHSOD1 ALTERS MITOCHONDRIAL STRUCTURE AND FUNCTION ............................... 29 4.1.1 MITOCHONDRIA ARE FRAGMENTED IN G93AHSOD1 MOTOR NEURONS .............. 29 4.1.2 MOTOR NEURON DEPENDENCY ON MITOCHONDRIAL CA2+ BUFFERING .............. 32 4.1.3 MITOCHONDRIA AND ER BUFFER GREAT PORTION OF CYTOSOLIC CA2+ .............. 34 4.1.4 MCU IS OVEREXPRESSED IN G93AHSOD1 MOTOR NEURONS ........................ 37 4.1.5 G93AHSOD1 ALTERS SPONTANEOUS CYTOSOLIC CA2+ ACTIVITY ...................... 40 4.1.6 KN-62 PROTECTED G93AHSOD1 MOTOR NEURONS AGAINST KAINATE ............ 42 4.2 ER-MITOCHONDRIA BRIDGE PROTEIN, SIG1R, MODULATES CYTOSOLIC CA2+ HOMEOSTASIS............................................................................................................ 45 4.2.1 EXPRESSION OF SIG1 R WAS INCREASED IN G93AHSOD1 MOTOR NEURONS ...45 4.2.2 SIG1R AGONISTS DIFFERENTLY AFFECT SIG1 R EXPRESSION IN G93AHSOD1 AND NONTG MOTOR NEURONS ....................................................................................... 46 4.2.3 SELECTIVE VULNERABILITY OF MOTOR NEURONS...........................................48 4.2.4 BRADYKININ-SENSITIVE INTRACELLULAR CA2+ STORES ARE REDUCED IN G93AHSOD1 SPINAL NEURONS .............................................................................. 49 4.2.5 PRE-084 DOES NOT ALTER BRADYKININ-SENSITIVE CA2+ STORES IN G93AHSOD1 SPINAL NEURONS.................................................................................................50 4.2.6 SA4503 RESCUES BRADYKININ-INDUCED CA2+ RELEASE IN G93AHSOD1 SPINAL NEURONS.................................................................................................51 4.2.7 PRE-084 DOES NOT AFFECT CYTOSOLIC CA2+ CLEARANCE FOLLOWING AMPAR STIMULATION.......................................................................................................54 4.2.8 SA4503 ACCELERATES CYTOSOLIC CA2+ CLEARANCE FOLLOWING AMPAR STIMULATION.......................................................................................................55 4.2.9 ER CA2+ STORAGE IS INCREASED IN G93AHSOD1 SPINAL NEURONS ............. 57 4.3 G93AHSOD1 DOES NOT INCREASE NUCLEAR DMA DAMAGE .................................. 59 5 DISCUSSION..................................................................................................62 5.1 MITOCHONDRIA IN ALS: A TRIGGER AND A TARGET ............................................... 62 5.1.1 MITOCHONDRIAL DYNAMICS ARE ALTERED IN G93AHSOD1 MOTOR NEURONS ...62 5.1.2 MOTOR NEURONS DEPEND ON MITOCHONDRIAL CA2+ BUFFERING ................... 63 5.1.3 MCU AS A TARGET AGAINST EXCITOTOXICITY ............................................. 64 5.2 SIG1R: A TOOL FOR ERMCC STABILIZATION IN ALS ............................................ 66 5.2.1 SIG1R IS DEREGULATED IN G93AHSOD1 MOTOR NEURONS .......................... 66 5.2.2 SIG1R AGONISTS DO NOT RESCUE AGAINST KAINATE-INDUCED EXCITOTOXICITY 67 5.2.3 SIG1 R MODULATES INTER-ORGANELLE CA2+ EXCHANGE ............................. 67 5.3 G93AHSOD1 DOES NOT INCREASE NUCLEAR DNA DAMAGE .................................. 69 5.4 ORGANELLE INTERPLAY IS DISTURBED IN THE PRESENCE OF G93AHSOD1 ................ 70 5.5 STRENGTHS AND LIMITATIONS OF THE STUDY ....................................................... 74 6 CONCLUSION AND OUTLOOK .................................................................... 75 7 LITERATURE.....................................................................................................I 8 APPENDIX..................................................................................................... XII 8.1 LIST OF FIGURES.................................................................................................XII 8.2 LIST OF TABLES.................................................................................................XIII 8.3 ACKNOWLEDGEMENTS......................................................................................XIV 8.4 PUBLICATIONS..................................................................................................XVI 8.4.1 ORIGINAL PUBLICATIONS.........................................................................XVI 8.4.2 REVIEWS............................................................................................ XVI 8.4.3 POSTER PRESENTATIONS....................................................................... XVII 8.4.4 TALKS................................................................................................ XVII 8.5 EHRENWOERTLICHE ERKLAERUNG ......................................................................... XVIII
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author	Tadić, Vedrana 1985-
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spelling	Tadić, Vedrana 1985- Verfasser (DE-588)1155271432 aut ER mitochondria calcium cycle (ERMCC) dysregulation in motor neurons of ALS mouse model as target for new therapeutic strategies by M.Sc. Vedrana Tadić Jena June 2017 VIII, 75, xvii Seiten Illustrationen 29 cm txt rdacontent n rdamedia nc rdacarrier Dissertation Friedrich Schiller University of Jena 2017 (DE-588)4113937-9 Hochschulschrift gnd-content B:DE-101 application/pdf http://d-nb.info/1155763106/04 Inhaltsverzeichnis DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=030607454&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis
spellingShingle	Tadić, Vedrana 1985- ER mitochondria calcium cycle (ERMCC) dysregulation in motor neurons of ALS mouse model as target for new therapeutic strategies
subject_GND	(DE-588)4113937-9
title	ER mitochondria calcium cycle (ERMCC) dysregulation in motor neurons of ALS mouse model as target for new therapeutic strategies
title_auth	ER mitochondria calcium cycle (ERMCC) dysregulation in motor neurons of ALS mouse model as target for new therapeutic strategies
title_exact_search	ER mitochondria calcium cycle (ERMCC) dysregulation in motor neurons of ALS mouse model as target for new therapeutic strategies
title_full	ER mitochondria calcium cycle (ERMCC) dysregulation in motor neurons of ALS mouse model as target for new therapeutic strategies by M.Sc. Vedrana Tadić
title_fullStr	ER mitochondria calcium cycle (ERMCC) dysregulation in motor neurons of ALS mouse model as target for new therapeutic strategies by M.Sc. Vedrana Tadić
title_full_unstemmed	ER mitochondria calcium cycle (ERMCC) dysregulation in motor neurons of ALS mouse model as target for new therapeutic strategies by M.Sc. Vedrana Tadić
title_short	ER mitochondria calcium cycle (ERMCC) dysregulation in motor neurons of ALS mouse model as target for new therapeutic strategies
title_sort	er mitochondria calcium cycle ermcc dysregulation in motor neurons of als mouse model as target for new therapeutic strategies
topic_facet	Hochschulschrift
url	http://d-nb.info/1155763106/04 http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=030607454&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA
work_keys_str_mv	AT tadicvedrana ermitochondriacalciumcycleermccdysregulationinmotorneuronsofalsmousemodelastargetfornewtherapeuticstrategies

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