. Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem. 2004 Apr 30;279(18):18614-22. PubMed.

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  1. Parkin and Mitochondria: Are They Allies in the War Against Parkinson’s Disease?
    This exciting study by Palacino and colleagues shows an alliance between two of the best-studied features of Parkinson's disease, namely, mitochondrial dysfunction and parkin. Since parkin was demonstrated to have E3 ubiquitin ligase activity (Shimura et al., 2000), many researchers hypothesized that an unknown substance that should be degraded by ubiquitination causes degeneration of nigral neurons. Supporting this hypothesis, several substrates of parkin, such as synphilin-1, CDC-rel1 and PAEL receptor, have been linked to nigral function (Zhang et al., 2000; Chung et al., 2001; see Imai et la., 2001 in ARF related news story). On the other hand, some groups, including the authors, reported that parkin null mice did not show apparent nigral dopaminergic neuron degeneration, but instead induced dysfunction to these neurons (Goldberg et al., 2003). Interestingly, neuronal death in Parkinson’s disease that results from ectopic expression of human α-synuclein is mitigated by coexpression of human parkin (see Petrucelli et al., 2002 in ARF related news story). Therefore, the net effect of loss of parkin on nigral neurodegeneration remains unclear. In this study, the authors demonstrated that deletion of parkin results in reduction of the proteins involved in mitochondrial function and oxidative balance. Recently, Darios and colleagues (2003) observed that PC32 cells overexpressing parkin are more resistant to cell death induced by ceramide. They observed that parkin acted by delaying mitochondrial swelling and subsequent cytochrome c release and caspase-3 activation observed in ceramide cell death. This exciting finding supports the idea that oxidative stress is an early pathophysiological process involved in the neurodegeneration of nigral dopaminergic neurons.

    This study shows the reduction of several components of NADH-ubiquinone oxidoreductase (complex I) or cytochrome oxidase (complex IV). Since these components are coded by mtDNA, which seems to be more susceptible to oxidative stress induced by mitochondria than those coded by nuclear DNA, this observation may not simply reflect leakage of reactive oxygen species from impaired electron transport chain. The normal number and morphology of mitochondrion are also consistent with this view. However, the study presented by Darios et al. (2003) showed an enrichment of parkin in the mitochondrial fraction and its association with the outer mitochondrial membrane, suggesting that parkin may promote the degradation of substrates localized in mitochondria. We hope that further study can solve this riddle.

    References:

    . Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nat Med. 2001 Oct;7(10):1144-50. PubMed.

    . Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria-dependent cell death. Hum Mol Genet. 2003 Mar 1;12(5):517-26. PubMed.

    . Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J Biol Chem. 2003 Oct 31;278(44):43628-35. PubMed.

    . An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell. 2001 Jun 29;105(7):891-902. PubMed.

    . Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem. 2004 Apr 30;279(18):18614-22. PubMed.

    . Parkin protects against the toxicity associated with mutant alpha-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons. Neuron. 2002 Dec 19;36(6):1007-19. PubMed.

    . Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet. 2000 Jul;25(3):302-5. PubMed.

    . 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. This is a great paper. The parkin mice were surprisingly phenotype-free, which seemed a nuisance, but may actually be helpful in this model, as Shen and her colleagues were able to look at proteome differences in the absence of changes in cell number. From my understanding, the original rationale was to look for proteins that change in abundance as a result of lack of E3 ligase activity. However, as the news summary points out, they identified two major groups of proteins: mitochondrial oxidative phosphorylation and oxidative stress response proteins.

    The mitochondrial proteins were generally downregulated. This is very exciting with reference to Leo Pallanck's group's paper showing a mitochondrial phenotype in parkin knockout flies (although mitochondria here are normal), and the reports of parkin suppressing mitochondrial damage by Alexis Brice's lab. Also, the hint from Peter Heutink's studies that DJ-1 is also mitochondrial in some circumstances may be relevant. Peroxiredoxins are also interesting; these are proteins that are often altered by oxidative stress; the other major one is DJ-1 (Mitsumoto et al., 2001). In many cases, the loss of one isoform correlates with the appearance of a more acidic form, which would be worth following up on.

    What isn't clear yet is how Parkin causes these changes. These proteins aren't known to be parkin substrates. In fact, there aren't any known substrates that would induce a mitochondrial phenotype; these would seem well worth looking for.

    View all comments by Mark Cookson
  3. The paper did not discuss the current limitation of proteome technology. Isn't it a coincidence that the proteins identified in this paper are mostly from mitochondria while most of the identifiable proteins on a 2D PAGE are also metabolism enzymes (see Lubec et al., 2003)?

    View all comments by Junchao Tong