Role of transport proteins in the pathogenesis of SCA3:
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| Format: | Thesis Book |
| Language: | English |
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Tübingen
Eberhard Karls Univ.
2014
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| Online Access: | Inhaltsverzeichnis |
| Physical Description: | 193 S. Ill., graph. Darst. 21 cm |
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| adam_text | ROLE OF TRANSPORT PROTEINS IN THE PATHOGENESIS OF SCA3
DISSERTATION
ZUR ERLANGUNG
DES GRADES EINES
DOKTORS DER NATURWISSENSCHAFTEN
DER MATHEMATISCH-NATURWISSENSCHAFTLICHEN FAKULTAT
UND
DER MEDLZLNISCHEN FAKULTAT
DER EBERHARD-KARLS-UNIVERSITAT TUBINGEN
VORGELEGT
VON
ANNA SERGEEVNA SOWA
AUS STUTTGART,
GERMANY
NOVEMBER 2014
1
HTTP://D-NB.INFO/1064705936
TABLE OF CONTENTS
TABLE OF CONTENTS 6
ABSTRACT 10
1. INTRODUCTION 11
1.1 DESCRIPTION OF SPINOCEREBELLAR ATAXIA TYPE
3/MACHADO JOSEPH
DISEASE 11
1.1.1
CLASSIFICATION AND
PREVALENCE OF SCA3 11
1.1.2 FAMILY
OF POLYGLUTAMINE EXPANSION
DISORDERS 13
1.1.3 SCA3 NEUROPATHOLOGY,
SYMPTOMS AND
MANIFESTATIONS 14
1.2 MJD/ATXN3 GENE 16
1.3 THE STRUCTURE AND
FUNCTION OF ATAXIN-3 PROTEIN 16
1.3.1
ATAXIN-3 IS CLEAVED BY CALPAINS AND
CASPASES 18
1.3.2 ATAXIN-3
IS RESPONSIBLE FOR
MAINTAINING CELLULAR PROTEIN HOMEOSTASIS 19
1.3.2.1 ATAXIN-3 IS AN IMPORTANT DEUBIQUITINATING ENZYME WITHIN THE
CELLULAR
ENVIRONMENT 19
1.3.2.2 TRANSCRIPTIONAL REGULATION IS AN IMPORTANT MECHANISM OF STRESS
RESPONSE
AND
PROTEIN HOMEOSTASIS
IN SCA3 21
1.4 NEURODEGENERATION, CELL DEATH, AND INFLAMMATION ALL PLAY A ROLE IN
SCA3
PATHOGENESIS 21
1.4.1
ATAXIN-3 TRANSLOCATES TO THE NUCLEUS
IN RESPONSE TO CELLULAR STRESS 22
1.4.2 PROTEIN CLEAVAGE IS AN IMPORTANT POTENTIAL CONTRIBUTOR TO ATAXIN-3
NUCLEAR
LOCALIZATION AND
TOXICITY 23 .
1.4.3 PROTEIN
AGGREGATION IS THE HALLMARK OF SCA3 AND
OTHER POLYGLUTAMINE DISEASE
....24
1.4.4 MITOCHONDRIAL RESPONSE PLAYS A LARGE ROLE IN ATAXIN-3 MEDIATED
NEURODEGENERATION 25
1.5 NUCLEAR CYTOPLASMIC TRANSPORT OF ATAXIN-3 IS AN IMPORTANT
PATHOLOGICAL MECHANISM
IN SCA3 26
1.5.1
MULTIPLE PATHWAYS REGULATE NUDEOCYTOPLASMIC
NEURONAL TRANSPORT 27
1.5.2 CELLULAR MECHANISMS FOR REGULATING NUCLEAR IMPORT AND EXPORT
INVOLVE A FAMILY OF
TRANSPORT PROTEINS AND THE
NUCLEAR PORE
COMPLEX 28
1.5.3 NUCLEAR LOCALIZATION
AND NUCLEAR
EXPORT SIGNALS
SERVE AS CARGO
RECOGNITION DOMAINS
FOR TRANSPORT PROTEINS 31
1.5.4 ATAXIN-3 CONTAINS ACTIVE NLS
AND NES
SITES WHICH SUGGEST
AN INTERACTION WITH
TRANSPORT PROTEINS 32
2. THESIS RATIONALE 35
3. MATERIALS AND METHODS 37
3.1 IN VITRO
EXPERIMENTS 37
3.1.1
CELL CULTURE MAINTENANCE 37
3.1.2 CELL CULTURE
TRANSFECTION 37
3.1.2.1 PLASMID PURIFICATION 37
3.1.2.2 TRANSIENT TRANSFECTION OF CELLS 38
3.1.2.3 STABLE TRANSFECTION
OF CELLS 38
3.1.3 PROTEIN ANALYSIS 39
3.1.3.1 FILTER TRAP AGGREGATE ANALYSIS
WITH CELL LYSATE 39
3.1.3.2 AGGREGATE COUNTING
IN LIVE CELLS 39
3.1.3.3 CYTOPLASMIC/NUCLEAR SEPARATION 39
3.1.3.4 WESTERN BLOT
ANALYSIS 40
3.1.3.5 BRADFORD ASSAY 41
3.1.4 IN VITRO VIABILITY ANALYSIS 41
3.1.4.1 PRESTO BLUE CELL
VIABILITY ASSAY 41
3.1.4.2 MTT (3-(4,5-DIMETHYLTHIAZOL-2-YL)-2,5-DIPHENYLTETRAZOLIUM
BROMIDE) CELL
PROLIFERATION ASSAY 42
3.1.5 IMMUNOFLUORESCENCE
OF CELLS 42
3.1.5.1 GENERAL IMMUNOFLUORESCENCE
PROTOCOL 42
3.1.5.2 LYSOTRACKER TO VISUALIZE LYSOSOMES 42
3.1.5.3 MICROSCOPY 42
3.1.6 PROTEIN
INTERACTION STUDIES 42
3.1.6.1 GST PULL
DOWN INTERACTION 43
3.1.6.2 GFP CO-PRECIPITATION ASSAY 43
3.1.6.3 ANALYSIS OF MASS
SPECTROMETRY DATA 43
3.1.7 NUCLEIC
ACID ANALYSIS 44
3.2 DROSOPHILA EXPERIMENTS 45
3.2.1
FLY LINES
HOUSING AND
BREEDING 45
3.2.1.1 HOUSING 45
3.2.1.2 DROSOPHILA LINES 46
3.2.1.3 MATING PROCEDURES 47
3.2.2 SALIVARY GLAND
EXPRESSION OF ATAXIN-3 47
3.2.3 BEHAVIOR ANALYSIS 47
3.2.3.1 ACTIVITY 47
3.2.3.2 GEOTAXIA ANALYSIS 48
3.2.4 EVALUATION
OF ROUGH
EYE PHENOTYPE
(REP) MODIFICATION 48
3.2.5 LONGEVITY ANALYSIS 48
3.2.6 QRT
SAMPLE PREPARATION 49
3.3 MOUSE ANALYSIS 50
3.3.1
MOUSE BREEDING
AND LINES 50
3.3.2 MOUSE
GENOTYPING 50
3.3.2.1 PCR GENOTYPING . . 50
3.3.2.2 QUANTITATIVE PCR GENOTYPING 51
3.3.3 ANIMAL
DETAILS 51
3.3.3.1 ANIMAL HOUSING 51
3.3.3.2 ANIMAL MARKING 51
3.3.4 BEHAVIOR TESTING 52
3.3.4.1 HOME CAGE ACTIVITY 52
3.3.4.2 ROTAROD: MOTOR SKILL LEARNING
AND
MOTOR COORDINATION ASSESSMENT 52
3.3.4.3 CATWALK: MEASURE
OF MOTOR FUNCTION AND COORDINATION 52
3.3.4.4 CLASPING BEHAVIOR 53
3.3.4.5 MOUSE WEIGHT CONTROLS 53
3.3.5 PREPARATION OF SAMPLES 53
3.3.5.1 SAMPLE PREPARATION
FOR PROTEIN ANALYSIS 53
3.3.5.2 HISTOLOGY 53
3.3.5.3 IMMUNOHISTOCHEMICAL STAINING 53
3.3.5.4 TOLUIDINE BLUE
STAINING 54
3.4 REVERSE PHASE PROTEIN
MICROARRAY ANALYSIS 54
3.5 TABLES OF EQUIPMENT, REAGENTS,
SOFTWARE USED 55
4. RESULTS 60
4.1 INTRACELLULAR SIGNALING
PATHWAYS ASSOCIATED WITH
AGGREGATION OF ATAXIN-3 61
4.1.1
LARGE SCREEN CAPTURES
CELLULAR DYSFUNCTION
IN ATAXIN-3-EXPANDED HEK
CELLS 61
4.2 TRANSPORT PROTEINS MODULATE ATAXIN-3 TOXICITY BY ALTERING LEVELS OF
AGGREGATED AND
SOLUBLE PROTEIN 64
4.2.1
CELL SCREEN IDENTIFIES
TRANSPORT PROTEINS WHICH INFLUENCE ATAXIN-3 AGGREGATION.64
4.2.2 VERIFICATION
OF TRANSPORT PROTEIN UPREGULATION 68
4.2.3 TRANSPORT PROTEINS
ALSO HAVE EFFECT
ON OTHER POLYQ PROTEINS 69
4.2.4 TRANSPORT PROTEINS
CAN CONTROL
SOLUBLE ATAXIN-3
LEVELS 70
4.2.5 DIFFERENCES
IN LC3 AND AUTOPHAGY LEVELS
MODULATED BY KPNA3 AND IP013 72
4.3 CELL VIABILITY AND PROTEIN LOCALIZATION CORRELATES WITH AGGREGATE
LOAD OF EXPANDED
ATAXIN-3 AND
OVEREXPRESSED TRANSPORT
PROTEINS 75
4.3.1
CELL VIABILITY
IS ALTERED
UPON TRANSPORT PROTEIN OVEREXPRESSION 76
4.3.2 KPNA3 INDUCES
A NUCLEAR TRANSLOCATION
OF ATAXIN-3
PROTEIN 79
4.4 TRANSPORT PROTEINS FORM
A COMPLEX WITH
ATAXIN-3 84
4.4.1
BIOINFORMATICS ANALYSIS AND PULL-DOWN ASSAY
SUGGEST INTERACTION BETWEEN ATAXIN-
3, KPNA3,
AND
PARTNER PROTEINS 84
4.5 SUMMARY OF IN
VITRO EXPERIMENTS WITH OVEREXPRESSION
OF TRANSPORT PROTEINS 89
4.6 DROSOPHILA MODEL CONFIRMS ABILITY OF TRANSPORT PROTEINS TO AFFECT
ATAXIN-3
LOCALIZATION 90
4.6.1 DROSOPHILA LINES PROVIDE ABILITY TO REGULATE SPATIAL AND TEMPORAL
EXPRESSION OF
TRANSGENES 90
4.6.2 DROSOPHILA MODEL CONFIRMS THAT KPNA3 IS ABLE TO AFFECT NUCLEAR
DISTRIBUTION OF
ATAXIN-3 94
4.7 SCA3 RELATED VIABILITY
AND NEURODEGENERATION
IS INFLUENCED
BY TRANSPORT PROTEINS 97
4.7.1
THE ROUGH EYE PHENOTYPE SHOWS SCA3
RELATED NEURODEGENERATION WHICH CAN BE
ALLEVIATED BY MODIFYING TRANSPORT PROTEINS 97
4.7.2 DROSOPHILA LIFESPAN
IS AFFECTED
BY TRANSPORT PROTEIN MODULATION 99
4.8 BEHAVIOR STUDIES IN DROSOPHILA SHOW EFFECT OF TRANSPORT PROTEINS ON
SCA3 BEHAVIOR
AND LOCOMOTOR
PHENOTYPES 105
4.9 SUMMARY OF IN VITRO AND DROSOPHILA EXPERIMENTS WITH MODULATION OF
TRANSPORT
PROTEINS 109
4.10 MOUSE MODEL DEMONSTRATES
THAT KPNA3 KNOCKOUT IS ABLE
TO RESCUE
BEHAVIOR AND
ACTIVITY ILL
4.10.1
GENERATION OF SCA3 KPNA3-/-
TRANSGENIC MICE ILL
4.10.2 HYPERACTIVITY AND ANXIETY BEHAVIOR IN MICE SHOWS A RESCUE WITH
KPNA3
KNOCKOUT 113
4.10.3 GAIT
DISORDERS IN SCA3 MICE ARE
IMPROVED WITH KPNA3 KNOCKOUT 116
4.10.4 ROTAROD PERFORMANCE AND LEARNING IS NOT IMPAIRED IN SCA3
MICE AND MILD
CLASPING PHENOTYPE
IS NOT
CHANGED WITH
KPNA3-/- 124
4.11 CRITICAL PATHWAY ACTIVATION
CAN EXPLAIN THE
EFFECT OF KPNA3 KNOCKOUT ON THE SCA3
PHENOTYPE IN MICE 126
4.11.1
LARGE SCREEN TO ANALYZE CHANGES IN PATHWAY ACTIVATION OF SCA3 MICE HELP
EXPLAIN
RESCUE EFFECT OF KPNA3-/- 126
4.11.2 WESTERN BLOT
ANALYSIS CONFIRMS VALIDITY
OF RPMA
RESULTS AND
ACTIVATION OF CLEAVED
CASPASES THROUGH XIAP
DOWNREGULATION 128
4.11.3 KPNA3
KNOCKOUT CHANGES
LOCALIZATION AND DECREASES
AGGREGATED AND SOLUBLE
ATAXIN-3 WHOLE BRAIN
LYSATE 131
4.11.4 SRC ACTIVATION IS ACCOMPANIED BY GLIAL INFLAMMATION IN FRONTAL
CORTEX AND NO LOSS
OF PURKINJE
CELLS OR GYRUS WIDTH 134
4.11.5 PATHWAY ACTIVATION CORRELATED TO METABOLIC DEFICITS IN SCA3 MICE
WHICH ARE
RESCUED BY KPNA3 KNOCKOUT 137
4.12 CORRELATIONS BETWEEN IN VITRO AND IN VIVO DATA PROVIDE A PICTURE OF
DEGENERATION
AND THE
ROLE OF TRANSPORT PROTEINS IN THAT DEGENERATION 138
5. DISCUSSION 141
5.1 UNDERSTANDING
THE PATHWAYS
OF CELLULAR DYSFUNCTION 142
5.2 TRANSPORT PROTEINS
ARE A WAY
OF ALTERING SCA3 PATHOGENICITY 146
5.3 THE IMPORT
PROTEIN KPNA3
IS ABLE
TO MODULATE SCA3 PATHOGENESIS 149
5.3.1 KPNA3
OVEREXPRESSION IS ABLE TO MODULATE THE SOLUBLE LEVELS OF ATAXIN-3 WHILE
DECREASING
CELLULAR VIABILITY 150
5.3.2 KPNA3 IS ABLE
TO ALTER THE LOCALIZATION OF ATAXIN-3 IN IN VITRO AND IN VIVO
MODELS 1S2
5.3.3 KPNA3 IS ABLE TO RESCUE BEHAVIORAL
PHENOTYPE OF DROSOPHIIA AND
MOUSE MODELS
OF
SCA3 155
5.3.4 KPNA3 KNOCKOUT
IS ABLE TO RESCUE GAIT ABNORMALITIES
IN SCA3 MOUSE MODEL 157
5.3.5 KPNA3 IS ABLE TO RESCUE VARIOUS CELLULAR PATHWAYS OF TOXICITY IN
MOUSE MODEL OF
SCA3 161
5.4 ENHANCING FUNCTION OF THE EXPORT PROTEIN CRM1 IS ABLE TO POSITIVELY
MODIFY
SCA3 167
5.5 IP013 AND TNPOL WARRANT MORE INVESTIGATION AS MODULATORS OF
POLYGLUTAMINE
DISEASE 169
6. CONCLUSION 173
ABBREVIATIONS 175
REFERENCES 176
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| spelling | Sowa, Anna Verfasser (DE-588)1062973062 aut Role of transport proteins in the pathogenesis of SCA3 vorgelegt von Anna Sergeevna Sowa Tübingen Eberhard Karls Univ. 2014 193 S. Ill., graph. Darst. 21 cm txt rdacontent n rdamedia nc rdacarrier Tübingen, Univ., Diss., 2014 (DE-588)4113937-9 Hochschulschrift gnd-content DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=027845517&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Sowa, Anna Role of transport proteins in the pathogenesis of SCA3 |
| subject_GND | (DE-588)4113937-9 |
| title | Role of transport proteins in the pathogenesis of SCA3 |
| title_auth | Role of transport proteins in the pathogenesis of SCA3 |
| title_exact_search | Role of transport proteins in the pathogenesis of SCA3 |
| title_full | Role of transport proteins in the pathogenesis of SCA3 vorgelegt von Anna Sergeevna Sowa |
| title_fullStr | Role of transport proteins in the pathogenesis of SCA3 vorgelegt von Anna Sergeevna Sowa |
| title_full_unstemmed | Role of transport proteins in the pathogenesis of SCA3 vorgelegt von Anna Sergeevna Sowa |
| title_short | Role of transport proteins in the pathogenesis of SCA3 |
| title_sort | role of transport proteins in the pathogenesis of sca3 |
| topic_facet | Hochschulschrift |
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