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Hwang, R.D., Wiemerslage, L., LaBreck, C.J., Khan, M., Kannan, K., Wang, X., Zhu, X., Lee, D., Fridell, Y.W. (2014). The neuroprotective effect of human uncoupling protein 2 (hUCP2) requires cAMP-dependent protein kinase in a toxin model of Parkinson's disease.  Neurobiol. Disease 69(): 180--191.
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Parkinson's disease (PD), caused by selective loss of dopaminergic (DA) neurons in the substantia nigra, is the most common movement disorder with no cure or effective treatment. Exposure to the mitochondrial complex I inhibitor rotenone recapitulates pathological hallmarks of PD in rodents and selective loss of DA neurons in Drosophila. However, mechanisms underlying rotenone toxicity are not completely resolved. We previously reported a neuroprotective effect of human uncoupling protein 2 (hUCP2) against rotenone toxicity in adult fly DA neurons. In the current study, we show that increased mitochondrial fusion is protective from rotenone toxicity whereas increased fission sensitizes the neurons to rotenone-induced cell loss in vivo. In primary DA neurons, rotenone-induced mitochondrial fragmentation and lethality is attenuated as the result of hucp2 expression. To test the idea that the neuroprotective mechanism of hUCP2 involves modulation of mitochondrial dynamics, we detect preserved mitochondrial network, mobility and fusion events in hucp2 expressing DA neurons exposed to rotenone. hucp2 expression also increases intracellular cAMP levels. Thus, we hypothesize that cAMP-dependent protein kinase (PKA) might be an effector that mediates hUCP2-associated neuroprotection against rotenone. Indeed, PKA inhibitors block preserved mitochondrial integrity, movement and cell survival in hucp2 expressing DA neurons exposed to rotenone. Taken together, we present strong evidence identifying a hUCP2-PKA axis that controls mitochondrial dynamics and survival in DA neurons exposed to rotenone implicating a novel therapeutic strategy in modifying the progression of PD pathogenesis.

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    Neurobiol. Disease
    Neurobiology of Disease
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