. Dopamine covalently modifies and functionally inactivates parkin. Nat Med. 2005 Nov;11(11):1214-21. PubMed.

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  1. Dopamine did it again. LaVoie and colleagues presented some compelling new evidence suggesting that dopamine may contribute to the demise of the same neurons that produce this essential neurotransmitter, this time by inactivating parkin. The authors analyzed the parkin species in dopaminergic cell lines and human tissues from normal and PD brains. In each case, they have convincingly demonstrated the presence of parkin species that are covalently modified by oxidized dopamine. The modification of parkin by dopamine quinone was specific, since several other cysteine-rich proteins and PD-related proteins were not similarly modified. In addition, this modification correlated with the accumulation of Triton-insoluble parkin. Furthermore, using an in vitro ubiquitination assay, the authors demonstrated that the highly reactive dopamine quinone inactivated parkin’s E3 ligase activity. Therefore, the authors proposed that parkin is a direct molecular target of oxidized dopamine, and the dopamine-induced loss of parkin activity represented a possible mechanism of the selective neurodegeneration in PD. This report echoes two earlier reports from the Lansbury’s lab (1) and us (2) suggesting that dopamine contributes to the α-synuclein toxicity. It also provides an interesting and exciting link between dopamine and another protein genetically linked to PD. In addition, this report strengthens the roles of reactive oxygen species in PD pathogenesis.

    Like many other interesting studies, this paper raises some new questions and will certainly stimulate additional discussions and future studies. Although the in vitro experiments in this study clearly demonstrated the covalent modification of parkin by dopamine quinone and the dopamine-induced decrease of soluble parkin, the results from the human brain tissues are less consistent. First, it is surprising that there was no detectable DA-conjugated parkin in the caudate-putamen, where dopamine is abundant, especially given that the insoluble parkin species accumulated in this region in both control and PD brains. Second, unlike in cultured dopaminergic cell lines, the presence of endogenous dopamine did not lead to deceased levels of soluble parkin in either the control or PD caudate-putamen, while dopamine presumably resulted in higher insoluble parkin species in this region.

    Interestingly, it is known that the dopamine content significantly decreases in PD brains. Therefore, the role of dopamine in parkin solubility in vivo, and the functional consequence caused by the change in parkin solubility remain to be clarified. Certainly, the accumulation of insoluble parkin may occur over a long period of time. Even so, the equivalent amount of a soluble (presumably the functional) pool of parkin among cortical and caudate tissues in normal and PD brains suggests a disease mechanism more complex than just the regulation of parkin solubility by DA. The DA-induced loss of E3 ligase activity, on the other hand, is a very interesting mechanism. It will be of great interest to pinpoint the site of the modification in parkin in vitro and in vivo using mass spectrometry, and to confirm the effects of DA modification on the solubility and the E3 ligase activity using a mutagenesis approach. In addition, identifying the modification site will also shed light on the specificity and selectivity of the parkin-DA conjugation, and potentially facilitate the design of inhibitors to alter the modification of parkin by DA.

    Another interesting observation presented in this paper is that DJ-1 and α-synuclein do not covalently bind oxidized dopamine. Like parkin, DJ-1 is a neuroprotective protein. The loss-of-function mutations in the human DJ-1 gene cause early onset PD. Several groups have suggested that cysteine 106 in the DJ-1 protein is sensitive to oxidative damage/modification, and is important for its normal function (3,4). This report has excluded the possibility that DA is the culprit potentially inactivating DJ-1 at C106. In addition, since DA theoretically modifies a cysteine residue within parkin, it will be of interest to determine why certain cysteine residues are particularly vulnerable to DA modification. A previous report (1) using recombinant α-synuclein indicates that DA modifies α-synuclein and stabilizes the toxic protofibrillar α-synuclein. However, DA-modified α-synuclein species were not detected in human brain tissues in this study. Therefore, the presence of potentially toxic DA-modified α-synuclein in vivo needs to be further confirmed.

    Overall, this paper provides an intriguing potential mechanism for selective parkin inactivation in PD. Given the unequivocal evidence that parkin is a ubiquitin E3 ligase, it is important to identify the authentic in vivo parkin substrates to fully understand their roles in PD.

    References:

    . Kinetic stabilization of the alpha-synuclein protofibril by a dopamine-alpha-synuclein adduct. Science. 2001 Nov 9;294(5545):1346-9. PubMed.

    . Dopamine-dependent neurotoxicity of alpha-synuclein: a mechanism for selective neurodegeneration in Parkinson disease. Nat Med. 2002 Jun;8(6):600-6. PubMed.

    . The 1.1-A resolution crystal structure of DJ-1, the protein mutated in autosomal recessive early onset Parkinson's disease. Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9256-61. PubMed.

    . The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):9103-8. PubMed.

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