Too Much of a Bad Thing: Parkin Target Induces PD

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

Comments

  1. A critical, frequently asked question for those studying neurodegenerative diseases is what makes particular neuronal subpopulations vulnerable during the disease. While there are many proposed hypotheses regarding this issue, it has been expected that particular genetic and proteomic components render specific neuronal subpopulations vulnerable. Parkinson’s disease (PD) is a good example of selective neuronal vulnerability wherein dopaminergic neurons exhibit selective cell death during the disease. A number of genetic abnormalities, including mutations in α-synuclein, parkin, and UCH-L1, have been implicated in familial forms of PD. Parkin mutations are responsible for a juvenile parkinsonism. Parkin functions to promote the degradation of specific target proteins, including CDCrel-1. Since CDCrel-1 functions in the secretory pathway Beites et al., 1999), it was proposed that increased levels of CDCrel-1 might be detrimental to dopamine neurons by impeding release of dopamine.

    To test this hypothesis, Bueler and colleagues overexpressed the CDCrel-1 protein in the nigrostriatal system and found specific loss of dopamine-producing neurons. Interestingly, pharmacologic inhibition of dopamine synthesis protected neurons from CDCrel-1-induced cell death. These intriguing findings suggest that parkin mutations lead to increased levels of CDCrel-1, inhibition of dopamine release, and dopamine-induced cell death. Increased levels of intracellular dopamine may induce oxidative injury and, ultimately, cell death. It remains unclear from the data if the increased levels of intracellular dopamine were contained in vesicular compartments or released into the cytoplasm. However, this study has identified a specific molecular mechanism that selectively targets dopaminergic neurons for cell death. It will be interesting to determine if dopamine neurons overexpressing CDCrel-1 can be protected via antioxidants. It will also be interesting to determine if α-synuclein mutations also impede proteasome degradation of CDCrel-1 and thus induce cell death via a similar dopamine-dependent mechanism. Prior studies have suggested that mutations in α-synuclein impair proper dopamine storage Lotharius and Brundin). Therefore, dopamine-containing cells may be selectively targeted in the majority of PD patients via a similar mechanism of altered proteasome function and/or vesicular trafficking, ultimately leading to dopamine-dependent cell death.

    References:

    Beites CL, Xie H, Bowser R, Trimble WS. The septin CDCrel-1 binds syntaxin and inhibits exocytosis. Nat Neurosci. 1999 May;2(5):434-9. PubMed.

    Lotharius J, Brundin P. Impaired dopamine storage resulting from alpha-synuclein mutations may contribute to the pathogenesis of Parkinson's disease. Hum Mol Genet. 2002 Oct 1;11(20):2395-407. PubMed.

    View all comments by Robert Bowser

  2. This paper by Dong and colleagues yields an impressive result that overexpression of CDCrel1 (also known as SEPT5) leads to the selective neurodegeneration of dopaminergic neurons. CDCrel1 is of unknown function, but was the first identified target protein of parkin, an E3 ubiquitin-ligase enzyme (Zhang et al., 2000). A variety of mutations in the parkin gene result in autosomal-recessive juvenile parkinsonism (AR-JP); these mutations result in loss of parkin function. One of the parkin substrates, Pael R, has been shown to be toxic and, consequently, its accumulation kills dopaminergic neurons (see ARF related news story; also see Yang et al., 2003). The function of CDCrel1, though, is not known, and so the finding that accumulation of these substrates may contribute to the selective neurodegeneration in dopaminergic neurons is quite interesting. In addition, the observation that CDCrel1 inhibits dopamine release provides an added, and unexpected, connection between CDCrel1 and dopamine physiology. This report provides some support for speculation that septins, such as CDCrel1, regulate vesicular exocytosis. In addition, this report provides an additional link between CDCrel1 and dopamine physiology, and might shed light into the pathophysiology of AR-JP. Further studies identifying whether overexpression of other parkin substrates results in the same selective neurodegenerative effects would be interesting and illuminate why the loss of parkin leads to AR-JP.

    References:

    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.

    Yang Y, Nishimura I, Imai Y, Takahashi R, Lu B. Parkin suppresses dopaminergic neuron-selective neurotoxicity induced by Pael-R in Drosophila. Neuron. 2003 Mar 27;37(6):911-24. PubMed.

    View all comments by Benjamin Wolozin

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References

News Citations

  1. New Players on the Parkinson's Field

Paper Citations

  1. 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.
  2. 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.
  3. 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.

Further Reading

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Primary Papers

  1. 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.

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