臺灣博碩士論文加值系統

帕金森氏症(Parkinson's disease)是最常見的神經元病變性運動障礙疾病，Phosphatase and tensin homologue (PTEN)-induced kinase 1(PINK1)的誤義突變(missense mutations)及截短突變(truncating mutations)與第六型遺傳型隱性帕金森氏症(PARK6)發病相關，同時PINK1的基因突變是導致早發型隱性帕金森氏症的第二常見主因。PINK1蛋白質主要表現在粒線體並且被認為扮演粒線體絲氨酸/蘇氨酸激酶(Ser/Thr protein kinase)的功能，同時執行神經保護作用對抗不同的細胞壓力。進一步探討突變PINK1所導致黑質多巴胺神經元退化的分子機轉能幫助發展第六型遺傳型帕金森氏症的治療策略。PINK1突變會導致體染色體隱性遺傳(autosomal recessive inheritance)並造成第六型遺傳型隱性帕金森氏症，而這些突變是屬於一個喪失功能(loss-of-function)的突變。因此，PINK1基因剔除鼠是合適的動物模式用以研究第六型遺傳型隱性帕金森氏症之分子病理機轉以及粒線體PINK1的生理功能。在本實驗中，我們已經利用基因標的策略(gene targeting strategy)配養出同型合子(homozygous) PINK1基因剔除鼠。接著，利用PINK1-/-基因剔除鼠的培養黑質多巴胺神經元來探討PINK1在黑質多巴胺細胞粒線體中執行神經保護功能之分子機轉及突變PINK1所引起的神經毒性之分子機轉。
PINK1被認為在於調控粒線體功能上扮演一個重要的角色。因此，我們推測喪失PINK1基因的表現會導致黑質多巴胺神經元的粒線體功能異常，為了證實此假說，我們利用共軛焦影像實驗(confocal microcopy imaging)測定比較正常(Wild-type)老鼠或PINK1-/-基因剔除鼠的培養黑質多巴胺神經元之粒線體膜電位 (mitochondrial membrane potential)、粒線體型態以及氧化活性物(reactive oxygen species)的生成情況。
利用粒線體膜電位螢光染劑TMRM進行共軛焦影像實驗發現，與正常老鼠培養黑質多巴胺神經元相比，PINK1-/-基因剔除鼠的培養黑質多巴胺神經元之TMRM螢光訊號強度明顯降低以及粒線體膜電位出現去極化的現象。藉由螢光染劑MitoTracker Green進行共軛焦影像實驗以觀察比較正常以及PINK1-/-基因剔除鼠黑質多巴胺神經元內粒線體型態，我們發現相較於正常老鼠黑質多巴胺神經元內絲狀(filamentous)、長線狀(long thread-like)的粒線體型態，PINK1-/-基因剔除鼠黑質多巴胺神經元則表現出斷片狀(fragmented)的粒線體。我們利用活性氧化物(reactive oxygen species)螢光染劑MitoSOX進行共軛焦影像實驗發現與正常老鼠的黑質多巴胺神經元比較起來，PINK1-/-基因剔除鼠的多巴胺神經元內基本活性氧化物合成量明顯增加。除此之外，我們也比較觀察到在氧化壓力劑H2O2的刺激下，PINK1-/-基因剔除鼠黑質多巴胺神經元內引發的活性氧化物合成量明顯高過於正常老鼠的黑質多巴胺神經元。
根據我們的實驗結果，在PINK1-/-基因剔除黑質多巴胺神經元內過量表現(overexpression)正常PINK1可以抑制活性氧化物的生成、回復粒線體膜電位以及長線狀的粒線體型態。粒線體膜電位在粒線體中是氧化磷酸化以及離子運輸的主要驅動力，而實驗結果指出在黑質多巴胺神經元中，PINK1對於維持粒線體膜電位是必要性的。同時PINK1也可藉由抑制活性氧化物合成而執行其神經保護的功能。除此之外，PINK1同時參予維持粒線體結構完整性以及調控粒線體分裂(fission)以及融合(fusion)。
相較於過量表現正常PINK1，在PINK1-/-基因剔除黑質多巴胺神經元內過量表現第六型遺傳型隱性帕金森氏症突變 (G309D), (E417G)或C端截短 (C delta 145) PINK1則失去挽救粒線體功能異常的功能以及抑制氧化壓力生成的能力。我們的實驗結果提出導致第六型遺傳型隱性帕金森氏症喪失功能的PINK1突變會造成粒線體功能異常以及氧化壓力上升進而導致黑質多巴胺神經元產生神經毒性。

Parkinson’s disease (PD) is the most common neurodegenerative motor disorder. Missense or truncating mutations of phosphatase and tesin homologue (PTEN)-induced kinase 1 (PINK1) gene are implicated in the pathogenesis of familial type 6 of Parkinson’s disease (PARK6) and that PINK1 is the second most frequent causative gene in early-onset Parkinson’s disease. PINK1 protein is mainly expressed in the mitochondria and has been proposed to function as a mitochondrial Ser/Thr protein kinase and exert neuroprotective effects against various cellular stresses. Better understanding the molecular basis of mutant PINK1-induced degeneration of substantia nigra (SN) dopaminergic neurons could lead to the development of effective PARK6 therapy. The autosomal recessive inheritance mode indicates a loss-of-function caused by PINK1 mutations is involved in the pathogenesis of PARK6. Thus, PINK1-deficient mice should be a valuable animal model to investigate the molecular pathogenesis of PARK6 and physiological functions of mitochondrial PINK1. In the present study, we have generated homozygous PINK1-/- mice using gene targeting strategy. Subsequently, primary SN dopaminergic neuronal culture of PINK1-null mice was prepared to study molecular mechanisms by which PINK1 exerts its neuroprotective effect within mitochondria and mutant PINK1 induces neurotoxicity of SN dopaminergic cells.
PINK1 is believed to play an important role in regulating mitochondrial functions. Therefore, absence of PINK1 expression is likely to cause mitochondrial dysfunction of SN dopaminergic neurons. To test this hypothesis, confocal microcopy imaging was performed to visualize mitochondrial membrane potential, mitochondrial morphology and ROS (reactive oxygen species) formation of cultured SN dopaminergic neurons prepared from wild-type or PINK1-/- mice.
Confocal imaging of potential sensitive dye tetramethylrhodamine methyl (TMRM) indicated that compared to cultured wild-type SN dopaminergic cells, a significant reduction in TMRM fluorescent signal and depolarized mitochondrial membrane potential was observed from SN dopaminergic neurons of PINK1-/- mice. Confocal MitoTracker Green staining was performed to visualize mitochondrial morphology of wild-type or PINK1-/- SN dopaminergic neurons. In contrast to filamentous and long thread-like mitochondria of wild-type SN dopaminergic neurons, fragmented mitochondria were observed from PINK1-deficient SN dopaminergic neurons. Compared to wild-type SN dopaminergic neurons, basal level of mitochondrial ROS formation, visualized by confocal MitoSOX staining, was significantly increased in PINK1-deficient SN dopaminergic neurons. Besides, the oxidative stressor H2O2-induced ROS production was greatly augmented in PINK1-null dopaminergic neurons than wild-type dopaminergic neurons.
Our results indicate that PINK1 is required for maintaining mitochondrial membrane potential of SN dopaminergic neurons, which is the driving force behind oxidative phosphorylation and ion transportation, and exerts neuroprotective effects by inhibiting ROS formation. PINK1 is also involved in maintaining the structural integrity and modulating fission-fusion of mitochondria.
Overexpression of wild-type PINK1 inhibited ROS formation, restored mitochondrial membrane potential and thread-like morphology of mitochondria in PINK1-deficient SN dopaminergic neurons. In contrast to wild-type PINK1, overexpression of PARK6 mutant (G309D), (E417G) or C-terminal truncated (C delta 145) PINK1 failed to rescue mitochondrial dysfunction and inhibit oxidative stress in PINK1-null SN dopaminergic cells. Our results provide the evidence that loss-of-function PARK6 mutation of PINK1 causes mitochondrial dysfunction, elevated oxidative stress and resulting neurotoxicity of SN dopaminergic cells.

Abstract (Chinese) v
Abstract (English) viii
Abbreviations xi
Contents xii
Ⅰ. Introduction 1
Ⅱ. Specific aims 10
Ⅲ. Methods and Materials 11
3.1 Construction of PINK1 knockout target vector and
generation of PINK1-deficient mice 11
3.2 Identification of PINK1-/- mice by Southern
blotting or PCR analysis of tail DNA 11
3.3 Northern blot analysis of PINK1 mRNA expression 12
3.4 RT-PCR analysis of PINK1 mRNA expression 13
3.5 Preparation of cultured substantia nigra neurons 13
3.6 Construction of point mutant or truncated PINK1 14
3.7 Preparation of recombinant adenoviruses 15
3.8 Confocal imaging of mitochondrial membrane
potential and reactive oxygen species (ROS)
formation in cultured substantia nigra (SN)neurons 16
3.9 Mitochondrial morphology 17
3.10 Stereological count of substantia nigra
dopaminergic neurons 17
3.11 Behavioral tests 18
3.12 Statistics 18
Ⅳ. Results 19
4.1 Generation of PINK1-defecient mice 19
4.2 Loss of PINK1 impairs mitochondrial function of
substantia nigra dopaminergic neurons by causing
a depolarization of mitochondrial membrane
potential 20
4.3 PINK1 deficiency leads to mitochondrial
fragmentation in substantia nigra dopaminergic
neurons 22
4.4 Loss of PINK1 increases basal level of reactive
oxygen species (ROS) and augments oxidative stress
in substantia nigra dopaminergic neurons 23
4.5 PINK1-deficient mice failed to exhibit the
symptoms of motor dysfunction and degeneration
of substantia nigra dopaminergic neurons 24
Ⅴ. Discussion 26
Ⅵ. References 35
Ⅶ. Figures 47

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