DrosophilaOverexpressing Parkin R275W Mutant Exhibits Dopaminergic Neuron Degeneration and Mitochondrial Abnormalities

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 agedependent 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.

Analysis of Leucine-rich repeat kinase 2 (LRRK2) and Parkinson protein 2 (parkin, PARK2) genes mutations in Slovak Parkinson disease patients

“…These studies suggest that parkin plays a key role in maintaining mitochondrial stability in certain cell types (Wang et al 2007).…”

Oxidative Stress in Parkinson's Disease; Parallels Between Current Animal Models, Human Studies and Cells

“…In some of the mouse knockout models, subtle abnormalities of the nigrostriatal pathway or the locus coeruleus noradrenergic system have been observed (Goldberg et al 2003, von Coelln et al 2006. Conversely, over-expression of mutant parkin produces a progressive loss of dopaminergic neurons in the nigrostriatal pathway in both mice and drosophila (Lu et al 2009, Sang et al 2007, Wang et al 2007). This suggests that some parkin mutants may act in a dominant negative fashion.…”

Successes of Modelling Parkinson Disease in Drosophila

“…The Drosophila parkin gene is highly expressed in the Drosophila central nervous system (Horowitz et al 2001;Bae et al 2003). In parkin mutants, the dopaminergic neurons degenerate (Greene et al, 2003;Cha et al, 2005;Whitworth et al, 2005;Wang et al, 2007). In flies that that overexpress some mutant forms of parkin, dopaminergic neurons degeneration occurs (Sang et al, 2007).…”

“…The male parkin mutants are sterile due to failure of mitochondrial activities during spermatogenesis (Riparbelli and Callaini, 2007). Reduction of neuronal-specific staining (either GFP or TH) and/or cell death has been reported in these parkin mutants (Greene et al, 2003;Cha et al, 2005;Whitworth et al, 2005;Wang et al 2007). The localization of this protein to the mitochondria (Darios et al, 2003) coupled with the consequences of parkin loss is a strong indication that it protects this organelle.…”