Characterization of PINK1-Parkin signaling pathway = PINK1-Parkin 신호전달계의 기능 연구

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PTEN-induced putative kinase 1 (PINK1) and Parkin, encoded by their respective genes associated with Parkinson’s disease (PD), are linked in a common pathway involved in the protection against mitochondrial dysfunction. However, not enough information on their biochemical relationship and physiological roles in mitochondria exists. Using both mammalian and Drosophila systems, I here demonstrated that the PINK1 kinase activity is required for its function on mitochondria. PINK1 regulates the localization of Parkin to the mitochondria in its kinase activity-dependent manner. In detail, Parkin phosphorylation by PINK1 on its linker region promotes its mitochondrial translocation, and the RING1 domain of Parkin is the critical region required for this occurrence. Next, I showed that mitochondria-translocated Parkin induces mitochondrial aggregation by inducing degradation of newly found target protein (NFTP). NFTP overexpression induces mitochondrial fragmentation, and knockdown of NFTP induces mitochondria fusion. Parkin degrades NFTP by ubiquitinating on Lys 200 and 201 residues and knockdown of Parkin induces an increase of NFTP protein amount. Down-regulation of NFTP by NFTP shRNA, compound A, B, and C blocks mitochondrial fragmentation in both parkin null or knockdown and PINK1 knockdown primary neurons. In conclusion, I discovered the mechanism by which PINK1 regulates Parkin and their protective effect on mitochondria by regulating NFTP. I believe that these results provide the central mechanism of PINK-Parkin-associated PD pathogenesis, which leads us one step closer to the development of effective treatment strategies for AR-JP.
Advisors
Chung, Jong-Kyeongresearcher정종경researcher
Description
한국과학기술원 : 생명과학과,
Publisher
한국과학기술원
Issue Date
2010
Identifier
418715/325007  / 020065819
Language
eng
Description

학위논문(박사) - 한국과학기술원 : 생명과학과, 2010.2, [ x, 132 p. ]

Keywords

Parkinson; mitochondria; Parkin; PINK1; drug; 약물; 파킨슨; 미토콘드리아; 파킨; 핑크

URI
http://hdl.handle.net/10203/27688
Link
http://library.kaist.ac.kr/search/detail/view.do?bibCtrlNo=418715&flag=dissertation
Appears in Collection
BS-Theses_Ph.D.(박사논문)
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