Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting about 0.3% to 1% of population, with an average age of onset of 55 and markedly increased prevalence and incidence with advancing age. The sporadic form accounts for most PD cases and the genetic component has only been appreciated recently. Although familial PD accounts for 3-10% of total cases, the convergence of implicated mechanisms from genetic mutations and environmental factors has vastly facilitated the studies on PD pathogenesis.
When mutations isolated in PINK1, a gene encoding a putative mitochondrial kinase, were isolated in autosomal recessive Parkinson's disease, this gene provided the first convergence of genetic factor and toxic model of PD—is mitochondrial dysfunction the main culprit? The initial hypothesis suggests that mutations can cause a loss of PINK1 kinase activity and eventually lead to mitochondrial dysfunction. This statement is corroborated with data demonstrating a role of PINK1 WT in maintaining normal mitochondrial morphology and physiology. To everyone's surprise, the mitochondrion is not the only subcellular compartment within which PINK1 resides, raising questions and concerns regarding the observation of cytosolic PINK1. The possibility of a dual subcellular localization puts current understanding of PINK1 cell biology under scrutiny. In this thesis I examine the dynamic kinetics of PINK1 processing and degradation and address PINK1 subcellular localization. Metabolic labeling analyses of PINK1 processing show that the expressions of PINK1 isoforms are tightly regulated and that PINK1 processing is dependent on intact mitochondrial membrane potential. Subcellular localization of PINK1 protein shows that the distribution of cleaved PINK1 isoforms from mitochondria to cytosol occurs after mitochondrial processing. I also identify cytosolic chaperone Hsp90 as an interacting protein of PINK1 for PINK1 stability, as the loss of Hsp90 activity decreases PINK1 levels due to degradation of PINK1 by the proteasome. The proteasomal degradation is a rare pathway for mitochondrial proteins. These findings collectively support a dual subcellular localization, implying that PINK1 can reside in the mitochondria and the cytosol. This raises intriguing functional roles that bridge these two cellular compartments and suggests that PINK1 is dual-functioning kinase.
|School:||The University of Chicago|
|School Location:||United States -- Illinois|
|Source:||DAI-B 69/07, Dissertation Abstracts International|
|Subjects:||Molecular biology, Neurosciences|
|Keywords:||Hsp90, Mitochondria, PINK1, Parkinson's disease, Valinomycin|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be