A report in press in the Journal of Biological Chemistry, published online February 24, adds to the growing body of evidence that traces the etiology of Parkinson's disease to the mitochondria. Jie Shen and colleagues at Brigham and Women's Hospital, Boston, reveal that many mitochondrial proteins are downregulated in mice lacking the protein parkin.

Parkin mutations, of course, have been linked to familial, early-onset Parkinson's disease since 1998 (see ARF related news story). Being a ubiquitin ligase, parkin has been generally thought to protect against this devastating disease by preparing other proteins for destruction. Much research has, therefore, focused on the relationship between parkin and proteins that end up in Lewy bodies. These are intracellular inclusions that foul up dopaminergic neurons of the substantia nigra, the part of the brain most affected by Parkinson's. However, in fruit fly models of the disease made by ablating parkin, dopaminergic neurons are hardly affected, while muscle mitochondria seem particularly compromised (see ARF related news story). More recently, Shen has shown that knocking out the gene in mice causes some physiological changes to the substantia nigra, but without the decimation of neurons that is observed in humans, and without altering likely parkin substrates, such as α-synuclein and synphilin (see Goldberg et al., 2003). So in mice, what are the biochemical consequences of losing parkin?

To address this issue, joint first authors James Palacino and Dijana Sagi adopted a comparative proteomics approach. They prepared extracts from the substantia nigra of both parkin-negative and normal mice, then separated the proteins by large, two-dimensional electrophoresis. When they analyzed these chromatographs, they could identify about 8,000 proteins, of which only 15 varied quantitatively between the two samples. Fourteen of these were downregulated in the parkin-deficient animals.

To identify these proteins, the authors subjected them to mass spectroscopy, and were surprised to find that nine of the 14 proteins are mitochondrial. Five are involved in oxidative phosphorylation, while four are involved in managing oxidative stress. The results suggest that parkin plays a major role in maintaining mitochondrial function. In support of this, the authors found that the parkin-deficient mice gained weight more slowly, had decreased serum antioxidant capacity, and increased protein and lipid peroxidation compared to normal animals. The last finding, in particular, suggests that parkin somehow protects against reactive oxygen species. As these are, for the most part, produced in the mitochondria, parkin may somehow prevent their production, possibly by maintaining flow through the electron transport chain; the authors also found that mitochondrial respiration is reduced in the mutant mice.

All told, these findings bolster the view that Parkinson's disease is connected with mitochondrial fitness. MPTP, for example, has been used for years to induce an experimental disease that models Parkinson's, and this chemical attacks the mitochondria, as does rotenone, a pesticide chemical that induces Parkinson's-like symptoms (see ARF related news story). And several groups have reported hints that polymorphisms in the DNA that is often forgotten—mitochondrial DNA—can alter the risk of Parkinson's disease (Van der Walt, 2001; Ross et al., 2003; Tanaka, 2002).—Tom Fagan


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Comments on News and Primary Papers

  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.

    View all comments by Kazuhiro Honda
  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.


    . Oxidized forms of peroxiredoxins and DJ-1 on two-dimensional gels increased in response to sublethal levels of paraquat. Free Radic Res. 2001 Sep;35(3):301-10. PubMed.

    . Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4078-83. 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.

  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)?


    . Proteomics in brain research: potentials and limitations. Prog Neurobiol. 2003 Feb;69(3):193-211. PubMed.


News Citations

  1. New Parkinson’s Gene
  2. New Parkinson's Fly Can’t Fly, Implicating Mitochondria
  3. A New Link Between Pesticides and Parkinson's Disease

Paper Citations

  1. . Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J Biol Chem. 2003 Oct 31;278(44):43628-35. PubMed.
  2. . Protein folding: a perspective for biology, medicine and biotechnology. Braz J Med Biol Res. 2001 Apr;34(4):419-35. PubMed.
  3. . mt4216C variant in linkage with the mtDNA TJ cluster may confer a susceptibility to mitochondrial dysfunction resulting in an increased risk of Parkinson's disease in the Irish. Exp Gerontol. 2003 Apr;38(4):397-405. PubMed.
  4. . Mitochondrial genotypes and cytochrome b variants associated with longevity or Parkinson's disease. J Neurol. 2002 Sep;249 Suppl 2:II11-8. PubMed.

Further Reading


  1. . Coding polymorphisms in the parkin gene and susceptibility to Parkinson disease. Arch Neurol. 2003 Sep;60(9):1253-6. PubMed.

Primary Papers

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