Characterization of drosophila PINK1 and parkin = 초파리 PINK1와 parkin 유전자의 기능 연구

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Parkinson’s disease (PD) is characterized by motor disturbances and dopaminergic (DA) neurodegeneration. parkin and PINK1, PD-associated genes, have been intensively studied to address its underlying molecular pathogenesis, but our understanding still remains unclear. Through generation and characterization of Drosophila mutants for PINK1, I show that PINK1 is required for mitochondrial integrity and function in both indirect flight muscles and dopaminergic neurons. Surprisingly, I found that PINK1 mutants share striking phenotypic similarities with parkin mutants. Indeed, transgenic expression of parkin dramatically ameliorates all PINK1 loss-of-function phenotypes, but not vice versa, implicating that Parkin acts downstream of PINK1 in maintaining mitochondrial integrity and function in both muscles and DA neurons. With the establishment of the PINK1-Parkin pathway, I further investigated the details in the relationship between PINK1 and Parkin. First, I examined whether the kinase activity of PINK1 is essential for the protection of mitochondria integrity and function in vivo. While expression of PINK1 wild type transgene almost fully rescued the impaired mitochondria of PINK1 mutants, the expression of the kinase inactive mutant (KD) could not rescue at all, which indicates that the kinase activity of PINK1 is essential for its mitochondrial function in vivo. Then, I examined whether this kinase activity is required for Parkin regulation. Through both biochemical and genetic analyses, I found that PINK1 induces Parkin translocation to mitochondria and subsequently promotes mitochondrial aggregation in a kinase-dependent manner. In conclusion, I discovered a functional interaction between PINK1 and Parkin, the mechanism by which PINK1 regulates Parkin and their protective effect on mitochondria. I believe that these results provide a greater understanding of the pathogenic mechanism of Parkinson’s disease.
Advisors
Chung, Jong-Kyeongresearcher정종경researcher
Description
한국과학기술원 : 생명과학과,
Publisher
한국과학기술원
Issue Date
2008
Identifier
310399/325007  / 020045834
Language
eng
Description

학위논문(박사) - 한국과학기술원 : 생명과학과, 2008.2, [ vii, 87 p. ]

Keywords

PINK1; Parkin; Drosophila; Parkinson`s disease; mitochondria; 핑크1; 파킨; 초파리; 파킨슨병; 미토콘드리아; PINK1; Parkin; Drosophila; Parkinson`s disease; mitochondria; 핑크1; 파킨; 초파리; 파킨슨병; 미토콘드리아

URI
http://hdl.handle.net/10203/27667
Link
http://library.kaist.ac.kr/search/detail/view.do?bibCtrlNo=310399&flag=dissertation
Appears in Collection
BS-Theses_Ph.D.(박사논문)
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