A <i>Drosophila</i> Model of Mutant Human Parkin-Induced Toxicity Demonstrates Selective Loss of Dopaminergic Neurons and Dependence on Cellular Dopamine
Tzu‐Kang Sang(National Tsing Hua University), Hui-Yun Chang, George Lawless(Centre for Movement Disorders), Anuradha Ratnaparkhi(Centre for Movement Disorders), Lisa Mee(Centre for Movement Disorders), Larry C. Ackerson, Nigel T. Maidment(University of California, Los Angeles), David E. Krantz(Center for Neuro-Oncology), George R. Jackson(University of California, Los Angeles)
Cited by 148Open Access
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.
Related Papers
Parkin functions as an E2-dependent ubiquitin– protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1
Yi Zhang, Jun Gao, Kenny K. K. Chung et al.|Proceedings of the National Academy of Sciences|2000|979