Parkinson's disease (PD) is a major neurodegenerative disorder affecting approximately 2% of the population over age 50, and the number of annual PD cases continues to rise along with the median age of the population. As the population in our society ages, we face the regrettable reality that effective medical treatment strategies for major chronic neurodegenerative disorders, including Parkinson's disease, are lacking. Determining the mechanisms of etiopathogenesis and selective nigrostriatal degeneration in PD is a formidable challenge. Emerging epidemiological and case control studies suggest that environmental factors, especially pesticides, are dominant risk factors in the etiology of sporadic, geriatric-onset Parkinson's disease. In this proposal, our preliminary data reveal that dopaminergic cells are susceptible to Dieldrin (a potential environmental risk factor for development of PD) -induced apoptosis, in which oxidative stress plays a causal role. We have also uncovered a novel apoptotic pathway involving caspase-3 dependent proteolytic cleavage of protein kinase Cdelta (PKCdelta) that not only mediates apoptosis in dopaminergic cells, but also influences key cellular events such as amplification of the apoptotic cascade through positive feedback activation and hyperphosphorylation of alpha-synuclein. We will extend our preliminary findings by pursuing the following Specific Aims: (I) characterize mitochondrial dysfunction and the subsequent activation sequence of key proapoptotic factors during dieldrin-induced oxidative stimulation in the mesencephalic dopaminergic cell model of Parkinson's disease, (ii) establish the proapoptotic function of caspase-3 dependent proteolytic activation of PKC5 in Dieldrin induced dopaminergic degeneration and to further investigate mechanisms underlying positive feedback amplification of the apoptotic signaling cascade by PKCdelta, (iii) obtain evidence to support the hypothesis that proteolytically activated PKCdelta hyperphosphorylates alpha-synuclein and thereby promotes protein aggregation, (iv) examine whether chronic exposure to Dieldrin in animal models induces caspase-3 dependent proteolytic cleavage of PKCdelta, alpha-synuclein aggregation, Lewy body formation and apoptotic cell death of dopaminergic neurons in the substantia nigra, and finally, (v) confirm the involvement of PKCdelta in nigral dopaminergic degeneration by using PKCdelta knockout animals and by targeted over-expression of PKCdelta and alpha-synuclein using a lentiviral delivery system in animal models. Together, results from the proposed systematic investigation will demonstrate the involvement of mitochondrial dysfunction, oxidative stress, apoptosis and protein aggregation in dopaminergic degeneration, and will further illuminate the mechanistic role of environmental factors in PD pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045133-03
Application #
6933790
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Refolo, Lorenzo
Project Start
2003-09-01
Project End
2007-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
3
Fiscal Year
2005
Total Cost
$312,075
Indirect Cost
Name
Iowa State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
005309844
City
Ames
State
IA
Country
United States
Zip Code
50011
Saminathan, Hariharan; Asaithambi, Arunkumar; Anantharam, Vellareddy et al. (2011) Environmental neurotoxic pesticide dieldrin activates a non receptor tyrosine kinase to promote PKCýý-mediated dopaminergic apoptosis in a dopaminergic neuronal cell model. Neurotoxicology 32:567-77
Song, C; Kanthasamy, A; Anantharam, V et al. (2010) Environmental neurotoxic pesticide increases histone acetylation to promote apoptosis in dopaminergic neuronal cells: relevance to epigenetic mechanisms of neurodegeneration. Mol Pharmacol 77:621-32
Sun, Faneng; Kanthasamy, Arthi; Song, Chunjuan et al. (2008) Proteasome inhibitor-induced apoptosis is mediated by positive feedback amplification of PKCdelta proteolytic activation and mitochondrial translocation. J Cell Mol Med 12:2467-81
Sun, Faneng; Kanthasamy, Arthi; Anantharam, Vellareddy et al. (2007) Environmental neurotoxic chemicals-induced ubiquitin proteasome system dysfunction in the pathogenesis and progression of Parkinson's disease. Pharmacol Ther 114:327-44
Anantharam, Vellareddy; Lehrmann, Elin; Kanthasamy, Arthi et al. (2007) Microarray analysis of oxidative stress regulated genes in mesencephalic dopaminergic neuronal cells: relevance to oxidative damage in Parkinson's disease. Neurochem Int 50:834-47
Zhang, Danhui; Kanthasamy, Arthi; Yang, Yongjie et al. (2007) Protein kinase C delta negatively regulates tyrosine hydroxylase activity and dopamine synthesis by enhancing protein phosphatase-2A activity in dopaminergic neurons. J Neurosci 27:5349-62
Sun, Faneng; Anantharam, Vellareddy; Zhang, Danhui et al. (2006) Proteasome inhibitor MG-132 induces dopaminergic degeneration in cell culture and animal models. Neurotoxicology 27:807-15
Kaul, Siddharth; Anantharam, Vellareddy; Yang, Yongjie et al. (2005) Tyrosine phosphorylation regulates the proteolytic activation of protein kinase Cdelta in dopaminergic neuronal cells. J Biol Chem 280:28721-30
Kaul, Siddharth; Anantharam, Vellareddy; Kanthasamy, Arthi et al. (2005) Wild-type alpha-synuclein interacts with pro-apoptotic proteins PKCdelta and BAD to protect dopaminergic neuronal cells against MPP+-induced apoptotic cell death. Brain Res Mol Brain Res 139:137-52
Latchoumycandane, Calivarathan; Anantharam, Vellareddy; Kitazawa, Masashi et al. (2005) Protein kinase Cdelta is a key downstream mediator of manganese-induced apoptosis in dopaminergic neuronal cells. J Pharmacol Exp Ther 313:46-55

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