title: A Drosophila model of mutant human parkin-induced toxicity demonstrates selective loss of dopaminergic neurons and dependence on cellular dopamine.
abstract: Mutations in human parkin have been identified in familial Parkinson's disease and in some sporadic cases. Here, we report that expression of mutant but not wild-type human parkin in Drosophila causes age-dependent, selective degeneration of dopaminergic (DA) neurons accompanied by a progressive motor impairment. Overexpression or knockdown of the Drosophila vesicular monoamine transporter, which regulates cytosolic DA homeostasis, partially rescues or exacerbates, respectively, the degenerative phenotypes caused by mutant human parkin. These results support a model in which the vulnerability of DA neurons to parkin-induced neurotoxicity results from the interaction of mutant parkin with cytoplasmic dopamine.
authors.affiliation: Neurogenetics Program, Department of Neurology, National Tsing Hua University, Taiwan, Republic of China.
authors.forename: Tzu-Kang
authors.initials: TK
authors.lastname: Sang
authors.forename: Hui-Yun
authors.initials: HY
authors.lastname: Chang
authors.forename: George M
authors.initials: GM
authors.lastname: Lawless
authors.forename: Anuradha
authors.initials: A
authors.lastname: Ratnaparkhi
authors.forename: Lisa
authors.initials: L
authors.lastname: Mee
authors.forename: Larry C
authors.initials: LC
authors.lastname: Ackerson
authors.forename: Nigel T
authors.initials: NT
authors.lastname: Maidment
authors.forename: David E
authors.initials: DE
authors.lastname: Krantz
authors.forename: George R
authors.initials: GR
authors.lastname: Jackson
mesh_terms: D000367:Age Factors; D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000473:pathology; D002452:Cell Count; D004195:Disease Models, Animal; D004298:Dopamine / Q000235:genetics / Q000502:physiology*; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology* / Q000633:toxicity; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D009154:Mutation; D009410:Nerve Degeneration / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D009474:Neurons / Q000473:pathology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology* / Q000633:toxicity
chemical_list: D029721:Drosophila Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D004298:Dopamine