A Drosophila model of mutant human parkin-induced toxicity demonstrates selective loss of dopaminergic neurons and dependence on cellular dopamine.
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.
Sang
Tzu-Kang
TK
Neurogenetics Program, Department of Neurology, National Tsing Hua University, Taiwan, Republic of China.
Chang
Hui-Yun
HY
Lawless
George M
GM
Ratnaparkhi
Anuradha
A
Mee
Lisa
L
Ackerson
Larry C
LC
Maidment
Nigel T
NT
Krantz
David E
DE
Jackson
George R
GR
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
D029721:Drosophila Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D004298:Dopamine