Genetic studies have revealed high level conservation of genes and pathways controlling the formation and patterning of muscle fibers during vertebrate and invertebrate development. Much less is known about the molecular mechanisms that help maintain the integrity and function of the different types of muscles after they are fully developed. Failure in the maintenance of muscle integrity and function can lead to debilitating muscle diseases. The goal of this proposal is to use Drosophila genetics to identify genes and pathways that control muscle maintenance. We have recently found that inactivation of the Drosophila homologue of human Pten-induced kinase 1 (Pink1) results in relatively selective degeneration of the indirect flight muscle (IFM), an extremely fast and metabolically active muscle. Muscle degeneration is preceded by dysfunction and degeneration of the mitochondria. Our genetic and biochemical studies indicate that Pink1 acts in the same pathway as Parkin, an E3 ubiquitin ligase also linked to mitochondria and muscle maintenance. We propose to carry out detailed biochemical and genetic analyses to understand the in vivo relationship between Pink1 and Parkin. In preliminary genetic interaction studies we have found that genes involved in regulating mitochondrial physiology can modify Pink1 mutant phenotypes. We propose to understand how these genes and Pink1 interact at the molecular and cellular levels. We have also identified genes that can enhance or suppress Pink1-associated muscle degeneration in an unbiased pilot genetic screen. We propose to expand this genetic modifier screen to systematically survey the Drosophila genome for new genes that function in the Pink1/Parkin pathway of mitochondria and muscle maintenance. Key genes will be selected and subjected to in depth phenotypic and molecular characterization and organized into genetic pathways. Understanding the function of the genes studied in this project will provide crucial insights into the fundamental mechanisms linking mitochondrial function with muscle maintenance. This will ultimately contribute to the treatment or prevention of degenerative muscle diseases, especially those with mitochondrial etiology. Given the association of Pink1 and Parkin to Parkinson's disease and the involvement of mitochondrial dysfunction in a host of neurodegenerative diseases, results to be obtained from this study will also be highly relevant to the maintenance of nervous system integrity.

Public Health Relevance

. The goal of this proposal is to understand the role of Pink1 protein in maintaining mitochondrial function and skeletal muscle integrity. Information to be gained from this study will help understand and ultimately treat muscle-related diseases, especially those with mitochondrial etiology, such as mitochondrial myopathy. Since Pink1 is also involved in Parkinson's disease, the information will also provide insights for the understanding and treatment of this devastating brain disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR054926-06
Application #
8243637
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Boyce, Amanda T
Project Start
2008-04-01
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
6
Fiscal Year
2012
Total Cost
$334,541
Indirect Cost
$125,453
Name
Stanford University
Department
Pathology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Gehrke, Stephan; Wu, Zhihao; Klinkenberg, Michael et al. (2015) PINK1 and Parkin control localized translation of respiratory chain component mRNAs on mitochondria outer membrane. Cell Metab 21:95-108
Lu, Bingwei; Gehrke, Stephan; Wu, Zhihao (2014) RNA metabolism in the pathogenesis of Parkinson׳s disease. Brain Res 1584:105-15
Rallis, Andrew; Lu, Bingwei; Ng, Julian (2013) Molecular chaperones protect against JNK- and Nmnat-regulated axon degeneration in Drosophila. J Cell Sci 126:838-49
Lee, Kyu-Sun; Wu, Zhihao; Song, Yan et al. (2013) Roles of PINK1, mTORC2, and mitochondria in preserving brain tumor-forming stem cells in a noncanonical Notch signaling pathway. Genes Dev 27:2642-7
Wu, Zhihao; Sawada, Tomoyo; Shiba, Kahori et al. (2013) Tricornered/NDR kinase signaling mediates PINK1-directed mitochondrial quality control and tissue maintenance. Genes Dev 27:157-62
Lee, Seongsoo; Imai, Yuzuru; Gehrke, Stephan et al. (2012) The synaptic function of LRRK2. Biochem Soc Trans 40:1047-51
Yu, Wendou; Polepalli, Jai; Wagh, Dhananjay et al. (2012) A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines. Hum Mol Genet 21:1384-90
Liu, Song; Sawada, Tomoyo; Lee, Seongsoo et al. (2012) Parkinson's disease-associated kinase PINK1 regulates Miro protein level and axonal transport of mitochondria. PLoS Genet 8:e1002537
Lee, Seongsoo; Wang, Ji-Wu; Yu, Wendou et al. (2012) Phospho-dependent ubiquitination and degradation of PAR-1 regulates synaptic morphology and tau-mediated Aβ toxicity in Drosophila. Nat Commun 3:1312
Pienaar, Ilse S; Lu, Bingwei; Schallert, Timothy (2012) Closing the gap between clinic and cage: sensori-motor and cognitive behavioural testing regimens in neurotoxin-induced animal models of Parkinson's disease. Neurosci Biobehav Rev 36:2305-24

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