A neuroprotective role of the human uncoupling protein 2 (hUCP2) in a Drosophila Parkinson's Disease model
| Autor: | Jenny Kwok, Lichuan Yang, Megha Sah, Yih-Woei C. Fridell, Kavitha Kannan, Denise Anamani, Marie E. Cantino, M. Flint Beal, Chibi Vijayan, Rafique Islam |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Mitochondrial DNA Substantia nigra Biology Neuroprotection Ion Channels lcsh:RC321-571 Animals Genetically Modified Mitochondrial Proteins Parkinsonian Disorders Human uncoupling protein 2 (hUCP2) Spargel Animals Humans Uncoupling Protein 2 lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Tyrosine hydroxylase Pars compacta Dopaminergic Neurons fungi Energy metabolism TFAM Mitochondrial oxidative phosphorylation Cell biology Disease Models Animal Drosophila melanogaster Neurology Biochemistry Mitochondrial biogenesis Female Neuron death Parkinson's Disease (PD) Dopaminergic (DA) neuron |
| Zdroj: | Neurobiology of Disease, Vol 46, Iss 1, Pp 137-146 (2012) |
| ISSN: | 0969-9961 |
| Popis: | Parkinson's disease (PD), caused by selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta, is the most common movement disorder. While its etiology remains unknown, mitochondrial dysfunction is recognized as one of the major cellular defects contributing to PD pathogenesis. Mitochondrial uncoupling protein 2 (UCP2) has been implicated in neuroprotection in several neuronal injury models. Here we show that hucp2 expression in Drosophila DA neurons under the control of the tyrosine hydroxylase (TH) promoter protects those flies against the mitochondrial toxin rotenone-induced DA neuron death, head dopamine depletion, impaired locomotor activity and energy deficiency. Under normal conditions, hUCP2 flies maintain an enhanced locomotor activity and have higher steady-state ATP levels suggesting improved energy homeostasis. We show that while no increased mitochondrial DNA content or volume fraction is measured in hUCP2 flies, augmented mitochondrial complex I activity is detected. Those results suggest that it is increased mitochondrial function but not mitochondrial biogenesis that appears responsible for higher ATP levels in hUCP2 flies. Consistent with this notion, an up-regulation of Spargel, the Drosophila peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) homologue is detected in hUCP2 flies. Furthermore, a Spargel target gene Tfam, the mitochondrial transcription factor A is up-regulated in hUCP2 flies. Taken together, our results demonstrate a neuroprotective effect of hUCP2 in DA neurons in a Drosophila sporadic PD model. Moreover, as the TH promoter activity is present in both DA neurons and epidermis, our results reveal that hucp2 expression in those tissues may act as a stress signal to trigger Spargel activation resulting in enhanced mitochondrial function and increased energy metabolism. |
| Databáze: | OpenAIRE |
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