Drosophila overexpressing parkin R275W mutant exhibits dopaminergic neuron degeneration and mitochondrial abnormalities.
Mutations in the parkin gene are a predominant cause of familial parkinsonism. Although initially described as a recessive disorder, emerging evidence suggest that single parkin mutations alone may confer increased susceptibility to Parkinson's disease. To better understand the effects of parkin mutations in vivo, we generated transgenic Drosophila overexpressing two human parkin missense mutants, R275W and G328E. Transgenic flies that overexpress R275W, but not wild-type or G328E, human parkin display an age-dependent degeneration of specific dopaminergic neuronal clusters and concomitant locomotor deficits that accelerate with age or in response to rotenone treatment. Furthermore, R275W mutant flies also exhibit prominent mitochondrial abnormalities in their flight muscles. Interestingly, these defects caused by the expression of human R275W parkin are highly similar to those triggered by the loss of endogenous parkin in parkin null flies. Together, our results provide the first in vivo evidence demonstrating that parkin R275W mutant expression mediates pathogenic outcomes and suggest the interesting possibility that select parkin mutations may directly exert neurotoxicity in vivo.
Wang
Cheng
C
Neurodegeneration Research Laboratory, National Neuroscience Institute, Singapore 308433.
Lu
Ruifeng
R
Ouyang
Xuezhi
X
Ho
Michelle W L
MW
Chia
William
W
Yu
Fengwei
F
Lim
Kah-Leong
KL
D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D001120:Arginine / Q000235:genetics; D004298:Dopamine / Q000235:genetics / Q000502:physiology*; D004330:Drosophila; D029721:Drosophila Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000473:pathology*; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014364:Tryptophan / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology
D029721:Drosophila Proteins; D014364:Tryptophan; D001120:Arginine; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D004298:Dopamine