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研究生：	張玉綾 Jhang, Yu-Ling
論文名稱：	探討小分子核糖核酸196a藉由調控粒線體功能達到脊髓小腦萎縮症第三型之保護功效 Investigate the Protective Effects of miR-196a on Spinocerebellar Ataxia Type 3 via Modulating Mitochondrial Functions
指導教授：	楊尚訓 Yang, Shang-Hsun
學位類別：	碩士 Master
系所名稱：	醫學院 - 生理學研究所 Department of Physiology
論文出版年：	2015
畢業學年度：	103
語文別：	英文
論文頁數：	75
中文關鍵詞：	脊髓小腦運動失調症第三型、分子核糖核酸196a 、粒線體功能
外文關鍵詞：	Spinocerebellar ataxia type 3 (SCA3), miR-196a, mitochondrial functions
相關次數：	點閱：88 下載：0
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脊髓小腦運動失調症第三型是最常見的顯性遺傳疾病，此疾病的成因是由於在ataxin-3蛋白上麩醯胺酸蛋白倍增突變所導致，突變的ataxin-3蛋白會形成聚集物並且造成粒線體功能受損的現象，至今仍然沒有有效的方法來減緩此疾病的進程。根據過去的研究發現小分子核糖核酸在神經疾病中扮演關鍵的角色，像是小分子核糖核酸196a能夠在亨丁頓舞蹈症和脊髓延髓肌肉萎縮症之病症中提供有益的功效，其中，亨丁頓舞蹈症和脊髓延髓肌肉萎縮症皆為多麩醯胺酸之疾病，由於脊髓小腦運動失調症第三型也是多麩醯胺酸之疾病的一種，因此我們提出了小分子核糖核酸196a能改善脊髓小腦運動失調症第三型進程的假說。為了探討分子核糖核酸196a對脊髓小腦運動失調症第三型的功效，首先建立了脊髓小腦運動失調症第三型之細胞及小鼠模式，結果中發現截短的ataxin-3 (101麩醯胺酸) 在小鼠神經瘤母細胞中會形成核內聚集並且導致神經細胞的死亡；而在髓小腦運動失調症第三型之小鼠模式生物的小腦中則表現出大量且病理性的聚集物。在建構完成脊髓小腦運動失調症第三型之細胞及小鼠模式後，將小分子核糖核酸196a過度表現在脊髓小腦運動失調症第三型之細胞模式中，隨後觀察到突變的ataxin-3與聚集物表現量皆有被抑制的現象。此外，小分子核糖核酸196a在脊髓小腦運動失調症第三型之細胞模式中，也能夠透過減少活性氧化物質來改善受損的粒線體功能，改善受損的粒線體功能中包含降低粒線體膜電位和減少粒線體分裂，隨後進而改善神經細胞的死亡。總結上述的結果，能夠發現小分子核糖核酸196a能夠抑制由突變ataxin-3所導致的聚集物，並且改善活性氧化物質的產生、受損的粒線體功能和神經的死亡率。因此，透過小分子核糖核酸196a所調節的治療方法能夠運用在脊髓小腦運動失調症第三型當中來提供保護的功效。

Spinocerebellar ataxia type 3 (SCA3), the most common dominantly inherited SCA, results from the expansion of polyglutamines (polyQ) in the ataxin-3 protein and leads to the formation of aggregates. In addition to aggregates, it has been proposed that the toxic polyQ protein may impair mitochondrial functions. Until now, there has been no effective therapy to delay SCA3 progression. According to previous studies, microRNAs (miRNAs) have played pivotal roles in neural diseases. For example, miRNA-196a (miR-196a) can provide beneficial effects in Huntington’s disease (HD) and Spinal-Bulbar Muscular Atrophy (SBMA), two polyQ diseases. Because SCA3 is also a polyQ disease, we hypothesize that miR-196a may improve the pathogenesis of SCA3 models. In order to study the effects of miR-196a in SCA3, we establish SCA3 cell and mouse models first. In the in vitro results, we find that the truncated ataxin-3 (T101Q) leads to the formation of intranuclear aggregates and neuronal death in N2a mouse neuroblastoma cells. In the in vivo results, the SCA3 mouse models express abundant and pathological aggregates in the cerebellum. Moreover, when miR-196a is overexpressed in SCA3 cell models, the T101Q and pathological aggregates are suppressed. Furthermore, miR-196a also decreases reactive oxygen species and improves the impairment of mitochondrial functions, including reducing mitochondrial membrane potential and mitochondrial fission to lower neuronal death in SCA3 cell models. Taken together, these results show that the T101Q leads to abundant and pathological aggregates, and the treatment of miR-196a ameliorates the aggregates, reactive oxygen species, impaired mitochondrial functions and neuronal death in SCA3 cell models. Therefore, miR-196a-mediated therapeutic methods can be utilized in this disease to provide protective effects.

                     Contents
Abstract..................................................I
Chinese Abstract.......................................II
Acknowledgments.......................................III
Contents...............................................IV
Figure contents......................................VIII
Chapter 1.	Introduction............................1
1.1	Background of spinocerebellar ataxia type 3 (SCA3)
........................................................1
1.1.1	Ataxin-3 Protein................................1
1.1.2	Impaired Protein Degradation in SCA3............3
1.1.3	Mitochondrial Dysfunction in SCA3...............4
1.1.4	Transcriptional Deregulation in SCA3............5
1.1.5	RNA Toxicity in SCA3............................5
1.1.6	Potential Therapeutic Strategies................5
1.2	MicroRNAs (miRNAs)..............................6
1.3	MiRNA biogenesis and mechanism..................6
1.4	The biological functions of miRNA...............8
1.5	MiRNAs in the brain.............................8
1.6	MiRNAs and SCA3.................................9
1.7	MiR-196a in the disease........................10
Chapter 2.	Objective and specific aims............13
2-1	Research rationals and hypothesis..............13
2-2	Specific aims..................................13
Chapter 3.	Materials and Methods..................14
3-1	DNA construction...............................14
3-2	DNA transformation.............................14
3-3	Plasmid DNA extraction.........................15
3-4	Cell culture...................................15
3-5	Transfection...................................16
3-6	Rapid, Efficient And Practical (REAP) method for 
subcellular fractionation of cells.....................17
3-7	Immunofluorescence analysis....................17
3-8	JC-1 Mitochondrial Membrane Potential Assay....18
3-9	Measurement of reactive oxygen species.........19
3-10	Mitochondrial morphology analysis..............19
3-11	MTT assay......................................20
3-12	Cell death rate analysis.......................20
3-13	Primary mouse cortical neuron culture..........20
3-14	Western blotting analysis......................21
3-15	Generation of transgenic mice..................24
3-16	Genotyping for transgenic mice.................24
3-17	Immunohistochemical analysis...................25
3-18	Fluoro-Jade B staining.........................26
3-19	Statistical analysis...........................27
Chapter 4.	Results................................28
4-1	Establishment of the SCA3 cell model...........28
4-2	MiR-196a suppresses the T101Q expression in vitro
.......................................................29
4-3	MiR-196a improves the impairment of mitochondrial
function in vitro......................................29
4-4	MiR-196a reduces the ROS in vitro..............32
4-5	MiR-196a lowers the neuronal death in vitro....33
4-6	The expression level of MiR-196a target genes..34
4-7	Generation of the SCA3 mouse model.............34
4-8	MiR-196a improves the MMP in vivo..............35
Chapter 5.	Discussion.............................37
Chapter 6.	Conclusion.............................41
Chapter 7.	References.............................42
Chapter 8.      Figures................................53









                Figure contents
Figure 1. The characterization of different ATXN3 constru
cts....................................................54
Figure 2. Protein expression of the F88Q and T101Q in cyt
oplasm and nuclear fractions at different time points..56
Figure 3. The distribution of T22Q and T101Q in N2a cells
.......................................................57
Figure 4. Protein expression of T22Q and T101Q after alte
ration of miR-196a in SCA3 cell models.................58
Figure 5. The cellular distribution of T101Q after overex
pression of miR-196a...................................59
Figure 6. Protein expression of mitochondrial fission and
fusion markers after treating with the T22Q and T101Q con
structs................................................60
Figure 7. Protein expression of mitochondrial fission and
fusion markers after alteration of miR-196a in the SCA3 
cell model.............................................62
Figure 8. The morphology of mitochondria after treating w
ith the T22Q and T101Q constructs in SH-SY5Y cells.....63
Figure 9. The morphology of mitochondria after alteration
of miR-196a in the SCA3 cell model.....................64
Figure 10. The mitochondrial membrane potential (MMP) aft
er alteration of miR-196a in the SCA3 cell model.......66
Figure 11. The reactive oxygen species (ROS) after altera
tion of miR-196a in the SCA3 cell model................67
Figure 12. The cell viability, cell death and cell prolif
eration after alteration of miR-196a in the SCA3 cell mod
el.....................................................68
Figure 13. The expression level of miR-196a target genes 
after alteration of miR-196a in the SCA3 cell model....70
Figure 14. Characterization of T22Q and T101Q transgenic 
mice...................................................71
Figure 15. The distribution of T22Q and T101Q in the cere
bellum of transgenic mice..............................72
Figure 16. Degenerative neurons in the cerebellum of SCA3
transgenic mice........................................73
Figure 17. The MMP after alteration of miR-196a in the SC
A3 primary culture model of mouse cortical neurons.....74
Figure 18. The working model in this study.............75                     
                                    

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