The neuroprotective effect of human uncoupling protein 2 (hUCP2) requires cAMP-dependent protein kinase in a toxin model of Parkinson's disease

Abstract

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.

Uncoupling Protein 2: A Key Player and a Potential Therapeutic Target in Vascular Diseases

“…Although the mechanism by which UCP2 is activated by ROS is not completely understood, reactive aldehydes derived from lipid peroxidation have been suggested to be the ROS able to induce UCP2 activation [ 28 ]. The known intracellular signaling pathways mediating UCP2 gene activation are the AMPK/SIRT1/PPAR α axis [ 29 ] and the cAMP-dependent protein kinase [ 30 , 31 ].…”

DNP, mitochondrial uncoupling, and neuroprotection: A little dab'll do ya

“…In addition to affects on cellular Ca 2+ signaling, neuronal UCPs may also influence other prominent signaling pathways including the cyclic AMP pathway. Thus, overexpression of UCP2 protected cultured primary dopaminergic neurons against the mitochondrial Complex I inhibitor rotenone, by a mechanism involving cyclic AMP-dependent protein kinase [51]. …”

Role of protein kinase A in regulating mitochondrial function and neuronal development: implications to neurodegenerative diseases

“…For instance, Dagda et al (Dagda, et al 2011) demonstrated that treatment of PINK1 deficient SH-SY5Y cells with pharmacological PKA activators or transient expression of a constitutively active form of mitochondrially-targeted PKA or D-AKAP1 reversed mitochondrial fragmentation. In a recent study, Hwang et al, (Hwang, et al 2014) reported that the mitochondrial membrane transport protein human uncoupling protein 2 (hUCP2) protected dopamine neurons in adult flies against rotenone -mediated mitochondrial fragmentation and toxicity by increasing intracellular cAMP levels. On the other hand, PKA inhibitors blocked the preserved mitochondrial integrity, movement, and cell survival induced by hUCP2 in hUCP2-expressing dopamine neurons exposed to rotenone.…”