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...  Read more

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.

References:
Mitsumoto A, Nakagawa Y, Takeuchi A, Okawa K, Iwamatsu A, Takanezawa Y. 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. Abstract

Greene JC, Whitworth AJ, Kuo I, Andrews LA, Feany MB, Pallanck LJ. Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4078-83. Abstract

Darios F, Corti O, Lücking CB, Hampe C, Muriel MP, Abbas N, Gu WJ, Hirsch EC, Rooney T, Ruberg M, Brice A. Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria-dependent cell death. Hum Mol Genet. 2003 Mar 1;12(5):517-26. Abstract

View all comments by Mark Cookson

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)?

References:
Lubec et al., Progress in Neurobiology, 2003, 69:193

View all comments by Junchao Tong