Mutations in the gene coding for Parkin cause a rare familial form of Parkinsonism, autosomal recessive juvenile Parkinsonism, that results in death of dopaminergic neurons in the substantia nigra. To understand how parkin causes disease, we need to understand the regulation and function of parkin. Our studies have lead us to investigate ubiquitination, which is a process that regulates protein degradation. We hypothesize that parkin regulates ubiquitination of other proteins in response to cellular contact with matrix proteins (such as collagen and laminin), and thereby controls regulation of the cytoskeleton and signal transduction by matrix proteins and their integrin receptors. Loss of parkin function could cause neurodegeneration by inhibiting matrix signaling and impairing maintenance of processes by neurons. Our preliminary data support this hypothesis by demonstrating that parkin-dependent ubiquitination is activated by cellular binding to matrix proteins. We have also identified parkin binding proteins that are associated with integrins. Conversely, cell lines that have reduced parkin expression (due to anti-sense parkin cDNA) decrease ubiquitination, retract processes upon cellular exposure to matrix proteins, and have abnormal signal transduction. The goal of this proposal is to investigate the regulation of ubiquitination by parkin (Aim 1), determine the role of parkin in regulating signaling in response to exposure of cells to matrix proteins (Aim 2) and identify common functional deficits associated with disease-related mutations in parkin. Interestingly, parkin is also linked to other forms of neurodegeneration. Parkin binds to alpha-synuclein, and in brains from donors with Parkinson's disease parkin accumulates in inclusions that contain alpha-synuclein, and shows 75% less binding of parkin to two proteins, filamin and hCDCrel2a. We intend to investigate the mechanism of parkin dysfunction by determining how parkin function is altered in Lewy body diseases, and whether oxidation or alpha-synuclein aggregation causes the dysfunction of parkin (Aim 3). The research in this proposal will provide insight into the function of parkin, determine how mutations in parkin produce disease, and provide a new window to understand the molecular pathophysiology of Parkinson's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS041786-05
Application #
6930860
Study Section
Special Emphasis Panel (ZNS1-SRB-W (02))
Program Officer
Murphy, Diane
Project Start
2001-06-01
Project End
2006-05-31
Budget Start
2004-07-01
Budget End
2006-05-31
Support Year
5
Fiscal Year
2004
Total Cost
$259,000
Indirect Cost
Name
Boston University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Dusonchet, Julien; Li, Hu; Guillily, Maria et al. (2014) A Parkinson's disease gene regulatory network identifies the signaling protein RGS2 as a modulator of LRRK2 activity and neuronal toxicity. Hum Mol Genet 23:4887-905
Di Domenico, Fabio; Sultana, Rukhsana; Ferree, Andrew et al. (2012) Redox proteomics analyses of the influence of co-expression of wild-type or mutated LRRK2 and Tau on C. elegans protein expression and oxidative modification: relevance to Parkinson disease. Antioxid Redox Signal 17:1490-506
Kim, Geunwon; Meriin, Anatoli B; Gabai, Vladimir L et al. (2012) The heat shock transcription factor Hsf1 is downregulated in DNA damage-associated senescence, contributing to the maintenance of senescence phenotype. Aging Cell 11:617-27
Chan, Diane; Citro, Allison; Cordy, Joanna M et al. (2011) Rac1 protein rescues neurite retraction caused by G2019S leucine-rich repeat kinase 2 (LRRK2). J Biol Chem 286:16140-9
Liu-Yesucevitz, Liqun; Bilgutay, Aylin; Zhang, Yong-Jie et al. (2010) Tar DNA binding protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue. PLoS One 5:e13250
Hsu, Cindy H; Chan, Diane; Greggio, Elisa et al. (2010) MKK6 binds and regulates expression of Parkinson's disease-related protein LRRK2. J Neurochem 112:1593-604
Saha, Shamol; Guillily, Maria D; Ferree, Andrew et al. (2009) LRRK2 modulates vulnerability to mitochondrial dysfunction in Caenorhabditis elegans. J Neurosci 29:9210-8
Frasier, M; Walzer, M; McCarthy, L et al. (2005) Tau phosphorylation increases in symptomatic mice overexpressing A30P alpha-synuclein. Exp Neurol 192:274-87
Poon, H Fai; Frasier, Mark; Shreve, Nathan et al. (2005) Mitochondrial associated metabolic proteins are selectively oxidized in A30P alpha-synuclein transgenic mice--a model of familial Parkinson's disease. Neurobiol Dis 18:492-8
Ved, Rina; Saha, Shamol; Westlund, Beth et al. (2005) Similar patterns of mitochondrial vulnerability and rescue induced by genetic modification of alpha-synuclein, parkin, and DJ-1 in Caenorhabditis elegans. J Biol Chem 280:42655-68

Showing the most recent 10 out of 19 publications