Genetic and genomic studies of Drosophila parkin mutants implicate oxidative stress and innate immune responses in pathogenesis.
Loss-of-function mutations of the parkin gene, which encodes a ubiquitin-protein ligase, are a common cause of autosomal recessive juvenile parkinsonism (ARJP). Previous work has led to the identification of a number of Parkin substrates that implicate specific pathways in ARJP pathogenesis, including endoplasmic reticulum (ER) stress and cell cycle activation. To test the involvement of previously implicated pathways, as well as to identify novel pathways in ARJP pathogenesis, we are using genetic and genomic approaches to study Parkin function in the fruit fly Drosophila melanogaster. In previous work, we demonstrated that Drosophila parkin null mutants exhibit mitochondrial pathology and flight muscle degeneration. To further explore the mechanisms responsible for pathology in parkin mutants, we analyzed the transcriptional alterations that occur during muscle degeneration and performed a genetic screen for parkin modifiers. Results of these studies indicate that oxidative stress response components are induced in parkin mutants and that loss-of-function mutations in oxidative stress components enhance the parkin mutant phenotypes. Genes involved in the innate immune response are also induced in parkin mutants. In contrast, our studies did not reveal evidence for cell cycle or ER stress pathway induction in parkin mutants. These results suggest that oxidative stress and/or inflammation may play a fundamental role in the etiology of ARJP.
Greene
Jessica C
JC
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
Whitworth
Alexander J
AJ
Andrews
Laurie A
LA
Parker
Tracey J
TJ
Pallanck
Leo J
LJ
D000818:Animals; D004331:Drosophila melanogaster; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D009154:Mutation; D018384:Oxidative Stress / Q000235:genetics; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D044767:Ubiquitin-Protein Ligases; C111567:parkin protein