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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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University of Pittsburgh Sch Medicine
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 BowserBoston University School of Medicine
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.
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