Mutations of parkin represent the most frequent cause of recessively-inherited Parkinson's disease (PD). Although parkin is expressed in many tissues including the brain, its mutations are linked to specific degeneration of nigral dopaminergic (DA) neurons and Parkinson's disease. Our long-term goal is to understand the function of parkin and its role in the selective degeneration of DA neurons in Parkinson's disease. Studies using parkin knockout mice and flies showed that loss of parkin disrupts mitochondrial functions. On the other hand, research on PD neurotoxins has demonstrated a critical role of mitochondrial dysfunction in PD pathogenesis. Thus, we would be able to gain significant insights into the molecular mechanism of Parkinson's disease by studying how parkin affects mitochondrial functions. Our previous studies have shown that parkin attenuates the toxicity of cytosolic dopamine by suppressing the transcription of monoamine oxidases (MAO), which are mitochondrial enzymes responsible for the oxidative deamination of dopamine. Our preliminary studies showed that parkin interacted with the transcription factor Estrogen-Related Receptor 1 (ERR1), which plays a significant role in transcription regulation of many mitochondrial proteins including MAO. Furthermore, we found that expression of COX4i2, isoforms 2 of subunit 4 of cytochrome C oxidase (a.k.a. Complex IV), was suppressed by parkin in a similar manner. Our microarray studies also showed that parkin altered the expression of many mitochondrial proteins encoded by the nuclear genome. Based on these lines of evidence, we hypothesize that parkin regulates the transcription of many nuclear-encoded mitochondrial proteins by interacting with transcription factors critically involved in mitochondrial gene expression. We will test this hypothesis by studying how parkin regulates the expression of monoamine oxidases and COX4i2, and examining the effects of parkin on the expression of other mitochondrial proteins. To investigate the cellular functions of parkin both in vitro and in vivo, we will use cell lines, parkin transgenic mice, parkin knockout mice, and cells derived from PD patients with parkin mutations. Knowledge gained from this study will significantly advance our understanding on how parkin affects mitochondrial functions and how such regulation goes awry when parkin is mutated. It will provide novel insights into the mechanisms by which mutations of parkin cause Parkinson's disease.

Public Health Relevance

Results generated from this proposal would significantly improve our understanding of parkin, a gene linked to early-onset Parkinson's disease. Our studies will also provide novel targets for the development of more effective therapies for Parkinson's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS061856-03
Application #
7997219
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Sieber, Beth-Anne
Project Start
2009-01-01
Project End
2013-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
3
Fiscal Year
2011
Total Cost
$339,784
Indirect Cost
Name
State University of New York at Buffalo
Department
Physiology
Type
Schools of Medicine
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Xu, Z; Jiang, H; Zhong, P et al. (2016) Direct conversion of human fibroblasts to induced serotonergic neurons. Mol Psychiatry 21:62-70
Ren, Yong; Jiang, Houbo; Hu, Zhixing et al. (2015) Parkin mutations reduce the complexity of neuronal processes in iPSC-derived human neurons. Stem Cells 33:68-78
Hu, Zhixing; Pu, Jiali; Jiang, Houbo et al. (2015) Generation of Naivetropic Induced Pluripotent Stem Cells from Parkinson's Disease Patients for High-Efficiency Genetic Manipulation and Disease Modeling. Stem Cells Dev 24:2591-604
Jiang, Houbo; Xu, Zhimin; Zhong, Ping et al. (2015) Cell cycle and p53 gate the direct conversion of human fibroblasts to dopaminergic neurons. Nat Commun 6:10100
Pu, Jiali; Frescas, David; Zhang, Baorong et al. (2015) Utilization of TALEN and CRISPR/Cas9 technologies for gene targeting and modification. Exp Biol Med (Maywood) 240:1065-70
Pliss, Artem; Kuzmin, Andrey N; Kachynski, Aliaksandr V et al. (2013) Nucleolar molecular signature of pluripotent stem cells. Anal Chem 85:3545-52
Pu, Jiali; Jiang, Houbo; Zhang, Baorong et al. (2012) Redefining Parkinson's disease research using induced pluripotent stem cells. Curr Neurol Neurosci Rep 12:392-8
Lee, Janine B; Wei, Jing; Liu, Wenhua et al. (2012) Histone deacetylase 6 gates the synaptic action of acute stress in prefrontal cortex. J Physiol 590:1535-46
Ren, Yong; Liu, Xiaojun; Lesage, Suzanne et al. (2012) The normal parkin sequence. Mov Disord 27:463-4
Cooper, Oliver; Seo, Hyemyung; Andrabi, Shaida et al. (2012) Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson's disease. Sci Transl Med 4:141ra90

Showing the most recent 10 out of 20 publications