The Neuroprotective Effect of Human Uncoupling Protein 2 (hUCP2) Requires cAMP dependent Protein Kinase in a Toxin Model of Parkinson's Disease
Date of Completion
Thomas T. Chen
Field of Study
Molecular and Cell Biology
Doctor of Philosophy
Parkinson’s disease (PD), caused by selective loss of dopaminergic (DAergic) 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 DAergic neurons in Drosophila. However, the 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 DAergic 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 DAergic 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 detected preserved mitochondrial network, mobility and fusion events in hucp2 expressing but not control DAergic neurons exposed to rotenone. hucp2 expression also increased intracellular cAMP levels. Thus, we hypothesized that cAMP-dependent protein kinase (PKA) might be an effector that mediates hUCP2- associated neuroprotection against rotenone. Indeed, preserved mitochondrial integrity, movement and cell survival observed in hucp2 expressing DAergic neurons exposed to rotenone were blocked by PKA inhibitors. Taken together, my work provides strong evidence identifying a hUCP2-PKA axis that controls mitochondrial dynamics and survival in DAergic neurons exposed to rotenone implicating a novel therapeutic strategy in modifying the progression of PD pathogenesis.
Hwang, Ran-Der, "The Neuroprotective Effect of Human Uncoupling Protein 2 (hUCP2) Requires cAMP dependent Protein Kinase in a Toxin Model of Parkinson's Disease" (2014). Doctoral Dissertations. 614.