The theme of investigations conducted within this award has been that the pathways which mediate and regulate the apoptotic naturally occurring cell death event during the development of dopamine neurons of the substantia nigra (SN) have potential relevance to the maintenance of viability of these neurons in adulthood, and thus to the pathogenesis of Parkinson's disease. We propose that understanding these developmentally important pathways will provide a scientific basis for the development of neuroprotective approaches to this disease. In this renewal application, we have two principal goals related to this theme. First, in Specific Aims I and II, we seek to determine the physiologic role of the Akt pathway in the development of SN dopamine neurons, and in the maintenance of their viability and functional integrity in adulthood in vivo. We further seek to explore the potential neuroprotective and restorative roles of Akt signaling in models of parkinsonism. This goal acknowledges the extensive evidence obtained in the in vitro context that Akt is a critical survival signaling mediator, and recognizes that there is minimal information available about its role in vivo. In addition, this goal is based on preliminary data which indicates a striking trophic effect of a constitutively active form of Akt on adult SN dopamine neurons, and an ability to substantially protect these neurons in a neurotoxin model. Our second goal is to address in Specific Aims III and IV two important fundamental issues in the neurobiology of glial cell line-derived neurotrophic factor (GDNF) for dopamine neurons. We have shown in the current funding period that GDNF may serve as a physiologic target-derived neurotrophic factor for dopamine neurons during the first phase of natural cell death, based on acute experiments with neutralizing antibodies. However, an important fundamental issue that must be addressed is whether selective loss of the GDNF receptor, GFRal, in SN dopamine neurons results in a lasting decrement in their number in the chronic setting. To address this issue, we have in the current funding period created mice with a floxed GFRal allele, which will permit its selective deletion in SN dopamine neurons. A second central current issue in the neurobiology of GDNF is whether GFRal regulates dopamine neuron development not only in cis (cell autonomously), but also in trans, from postsynaptic striatal neurons. This issue will be addressed with both a selective deletion of GFRal receptors in striatal neurons, and a selective overexpression using a double transgenic approach. These investigations will define the roles of these important signaling molecules in the normal development of SN dopamine neurons, and will provide a basis for their potential use in neuroprotective approaches for Parkinson's disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Sieber, Beth-Anne
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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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
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
Cheng, Hsiao-Chun; Burke, Robert E (2010) The Wld(S) mutation delays anterograde, but not retrograde, axonal degeneration of the dopaminergic nigro-striatal pathway in vivo. J Neurochem 113:683-91
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

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