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PMID:17687034

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Citation

Wang, C, Lu, R, Ouyang, X, Ho, MW, Chia, W, Yu, F and Lim, KL (2007) Drosophila overexpressing parkin R275W mutant exhibits dopaminergic neuron degeneration and mitochondrial abnormalities. J. Neurosci. 27:8563-70

Abstract

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.

Links

PubMed Online version:10.1523/JNEUROSCI.0218-07.2007

Keywords

Amino Acid Substitution/genetics; Animals; Animals, Genetically Modified; Arginine/genetics; Dopamine/genetics; Dopamine/physiology; Drosophila; Drosophila Proteins/biosynthesis; Drosophila Proteins/genetics; Drosophila Proteins/physiology; Gene Expression Regulation/physiology; Humans; Mitochondria/genetics; Mitochondria/pathology; Mutation; Nerve Degeneration/genetics; Nerve Degeneration/metabolism; Nerve Degeneration/pathology; Tryptophan/genetics; Ubiquitin-Protein Ligases/biosynthesis; Ubiquitin-Protein Ligases/genetics; Ubiquitin-Protein Ligases/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DROME:PRKN

involved_in

GO:0008344: adult locomotory behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:PRKN

involved_in

GO:0007005: mitochondrion organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:PRKN

involved_in

GO:0070050: neuron cellular homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q7KTX7

involved_in

GO:0007005: mitochondrion organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q7KTX7

involved_in

GO:0070050: neuron cellular homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q7KTX7

involved_in

GO:0008344: adult locomotory behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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