title: A neuroprotective role of the human uncoupling protein 2 (hUCP2) in a Drosophila Parkinson's disease model.
abstract: 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.
authors.affiliation: Department of Allied Health Sciences, University of Connecticut, 358 Mansfield Road, Storrs, CT 06269, USA.
authors.forename: Rafique
authors.initials: R
authors.lastname: Islam
authors.forename: Lichuan
authors.initials: L
authors.lastname: Yang
authors.forename: Megha
authors.initials: M
authors.lastname: Sah
authors.forename: Kavitha
authors.initials: K
authors.lastname: Kannan
authors.forename: Denise
authors.initials: D
authors.lastname: Anamani
authors.forename: Chibi
authors.initials: C
authors.lastname: Vijayan
authors.forename: Jenny
authors.initials: J
authors.lastname: Kwok
authors.forename: Marie E
authors.initials: ME
authors.lastname: Cantino
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
authors.forename: Yih-Woei C
authors.initials: YW
authors.lastname: Fridell
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D004331:Drosophila melanogaster; D005260:Female; D006801:Humans; D007473:Ion Channels / Q000235:genetics / Q000502:physiology*; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics / Q000502:physiology*; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D000071246:Uncoupling Protein 2
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604389:UCP2 protein, human; D000071246:Uncoupling Protein 2