Shedding light on why mutations in parkin protein might cause familial Parkinson's disease, a study in the October 6 online PNAS shows how overexpression of one of parkin's targets can cause degeneration of dopamine neurons in vivo.
Hansruedi Bueler and colleagues of the University of Zurich and the Swiss Federal Institute of Technology in Schwerzenbach addressed the hypothesis that both familial and sporadic PD involve disruption of the proteosome system for degrading unwanted proteins. Parkin seems to play a role in tagging some of these proteins with ubiquitin, labeling them for proteosome degradation (see ARF related news story). The suggestion is that some of these proteins, if left intact, can cause cell death in PD.
Using a viral vector, Bueler's team delivered the gene for one of parkin's targets-CDCrel-1-into the subtantia nigra of rats. Overexpression of the protein led to a progressive loss of nigral dopamine neurons, and a corresponding decline in striatal dopamine levels.
One idea that has been advanced is that increased CDCrel-1 contributes to the loss of striatal dopamine levels because it inhibits the release of dopamine from the nigral projections (Zhang et al., 2000; Schweitzer et al., 1995). Of special interest is the fact that CDCrel-1 belongs to the septin family, proteins that have been implicated in the recruitment or docking of vesicles at the cell membrane. The researchers found support for this idea by expressing CDCrel-1 in PC12 cells, which synthesize dopamine and store it in vesicles. These cells can be induced to release dopamine by exocytosis, but with excess CDCrel-1 expression, Bueler's team discovered, secreted dopamine was reduced.
This observation led the researchers to investigate another hypothesis-that dopamine itself is an accessory in cell death in PD Junn and Mouradian, 2001). In support of this idea, the researchers found that when they tried to “neutralize” the in-vivo overexpression of CDCrel-1 in the rat substantia nigra with an inhibitor of dopamine synthesis, both the survival of nigral neurons and the density of nigral projections to the striatum increased. By contrast, nondopaminergic neurons of the globus pallidus were unaffected by overexpression of CDCrel-1.—Hakon Heimer
- Zhang Y, Gao J, Chung KK, Huang H, Dawson VL, Dawson TM. Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proc Natl Acad Sci U S A. 2000 Nov 21;97(24):13354-9. PubMed.
- Schweitzer ES, Sanderson MJ, Wasterlain CG. Inhibition of regulated catecholamine secretion from PC12 cells by the Ca2+/calmodulin kinase II inhibitor KN-62. J Cell Sci. 1995 Jul;108 ( Pt 7):2619-28. PubMed.
- Junn E, Mouradian MM. Apoptotic signaling in dopamine-induced cell death: the role of oxidative stress, p38 mitogen-activated protein kinase, cytochrome c and caspases. J Neurochem. 2001 Jul;78(2):374-83. PubMed.
No Available Further Reading
- Dong Z, Ferger B, Paterna JC, Vogel D, Furler S, Osinde M, Feldon J, Büeler H. Dopamine-dependent neurodegeneration in rats induced by viral vector-mediated overexpression of the parkin target protein, CDCrel-1. Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12438-43. PubMed.