The theme of our investigations has been that the molecular pathways of programmed cell death (PCD) may be relevant to the pathogenesis of Parkinson's disease and allied disorders. In recent years it has also become apparent that PCD regulates viability in cell-based therapeutic approaches, including tissue implants and neural stem cells. There has been tremendous growth in our knowledge of the molecular basis of PCD. However, most of this knowledge derives from relatively simple in vitro systems. While there are universal aspects of PCD mechanisms, it is nevertheless also clear that PCD is context dependent. It is therefore essential to translate this new knowledge to the in vivo context. A unique aspect of our approach is to examine PCD in postmitotic, phenotypically defined dopamine (DA) neurons in living brain. We will investigate two themes related to regulation and effector mechanisms of cell death in these neurons. While there is evidence that natural cell death (NCD) in DA neurons is regulated by striatum-derived neurotrophic support, the nature of these factors remains unknown. Theme 1 will examine the possibility that GDNF or neurturin (NTN) may serve as such factors.
Our first Aim will examine the effect of increased striatal expression of GDNF, in a unique temporally-regulated bi-transgenic model, on the mature number of DA neurons.
The second Aim will determine whether endogenous striatal GDNF regulates the magnitude of NCD in DA neurons, through the application of """"""""knock down"""""""" approaches.
Our third Aim will directly compare the potency of GDNF and NTN to suppress apoptotic death in a developmental axotomy model. Theme 2 will seek to identify important proteases mediating PCD in DA neurons in vivo. We have shown that activated caspase-3 is expressed in apoptotic DA neurons.
In Aim I V, we will examine the functional significance of its expression, by studying the magnitude and protein cleavage characteristics of NCD, and the size of DA progenitor pools, in caspase-3 null animals. Many in vitro studies have shown that caspases-independent pathways exist.
In Aim V, we will examine expression of the proteasome complex in PCD in DA neurons in vivo. The new knowledge gained by the studies outlined in this application will have direct implications for concepts of pathogenesis of Parkinson's disease and for approaches to optimizing cell-based treatments.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-3 (01))
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Oliver, Eugene J
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Columbia University (N.Y.)
Schools of Medicine
New York
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Burke, Robert E; O'Malley, Karen (2013) Axon degeneration in Parkinson's disease. Exp Neurol 246:72-83
Chen, Xiqun; Tagliaferro, Patricia; Kareva, Tatyana et al. (2012) Neurotrophic effects of serum- and glucocorticoid-inducible kinase on adult murine mesencephalic dopamine neurons. J Neurosci 32:11299-308
Kim, Sang Ryong; Kareva, Tatyana; Yarygina, Olga et al. (2012) AAV transduction of dopamine neurons with constitutively active Rheb protects from neurodegeneration and mediates axon regrowth. Mol Ther 20:275-86
Kim, Sang Ryong; Ries, Vincent; Cheng, Hsiao-Chun et al. (2011) Age and ýý-synuclein expression interact to reveal a dependence of dopaminergic axons on endogenous Akt/PKB signaling. Neurobiol Dis 44:215-22
Kholodilov, Nikolai; Kim, Sang Ryong; Yarygina, Olga et al. (2011) Glial cell line-derived neurotrophic factor receptor-?1 expressed in striatum in trans regulates development and injury response of dopamine neurons of the substantia nigra. J Neurochem 116:486-98
Cheng, Hsiao-Chun; Kim, Sang Ryong; Oo, Tinmarla F et al. (2011) Akt suppresses retrograde degeneration of dopaminergic axons by inhibition of macroautophagy. J Neurosci 31:2125-35
Kim, Sang Ryong; Chen, Xiqun; Oo, Tinmarla F et al. (2011) Dopaminergic pathway reconstruction by Akt/Rheb-induced axon regeneration. Ann Neurol 70:110-20
Cheng, Hsiao-Chun; Ulane, Christina M; Burke, Robert E (2010) Clinical progression in Parkinson disease and the neurobiology of axons. Ann Neurol 67:715-25
Burke, Robert E (2010) Intracellular signalling pathways in dopamine cell death and axonal degeneration. Prog Brain Res 183:79-97
Burke, Robert E (2010) Evaluation of the Braak staging scheme for Parkinson's disease: introduction to a panel presentation. Mov Disord 25 Suppl 1:S76-7

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