. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature. 2006 Jun 29;441(7097):1162-6. PubMed.


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  1. A central goal for many of us working on the molecular biology of Parkinson disease (PD) has been to identify a central pathway linking the protein products of genes known to cause this disease when mutated. Two papers recently published in Nature describe a very convincing connection between two proteins unequivocally linked to parkinsonism (Clark et al., 2006; Park et al., 2006). The two studies show that knockouts in the Drosophila PINK1 and parkin homologues both result in an overlapping phenotype of degeneration that prominently includes mitochondrial dysfunction. Furthermore, parkin overexpression can rescue the PINK1 knockout phenotype, but not vice versa, suggesting that these two proteins are in a common pathway with parkin downstream of PINK1. These findings show, in a paradigm similar to that seen in the molecular genetics of AD, that identifying different genetic causes of disease may lead to the elucidation of a common molecular pathogenesis.

    These data also add credence to the idea that mitochondrial dysfunction is central to several forms of PD/parkinsonism. From a genetic perspective, there has been recent support for this, ranging from evidence that polymerase G mutations, which presumably lead to increased mutation of the mitochondrial genome, may be a cause of early onset PD (Davidzon et al., 2006), to the observation that somatic deletion mutations in the mitochondrial genome are more common in neurons of the substantia nigra compared to several other neuronal populations (Bender et al., 2006; Kraytsberg et al., 2006). While the latter data explicitly suggest that these mutations are not the cause of PD, as they are found both in individuals who died of PD and neurological controls, one wonders whether they contribute to the preferential vulnerability of nigrostriatal dopaminergic neurons.

    There are two unresolved issues about this work. The first is one of conservation of function across species. It is interesting that the Drosophila PINK1 and parkin models have a much more extreme phenotype than do human patients. In fact, the muscle loss in the fly models seems at least superficially reminiscent of some of the mitochondrial disorders where muscle and optic nerve atrophy are common problems. However, human parkin and PINK1 patients have a more restricted area of damage, namely nigral neurons, without extensive damage to other systems, as far as we know. Why is there such a dramatic species difference? One possibility is that the two sets of genes are not perfect functional homologues. Both kinases and E3 ligases are large gene families, and it may be a simplification to infer that they have the same targets in mammals and invertebrates (see previous ARF comment). Though it may be much simpler and very useful to reconstruct pathways in an organism with lesser redundancy, it does mean that we have to apply some caution in using these models to predict human pathways when we don’t understand the intervening steps. One interesting experiment would be to see if human parkin rescued the fly phenotypes; if so, this would imply that the two proteins are strict functional orthologues. Showing that E3 ligase-deficient parkin mutations fail to do so would also be important in elucidating how this enzyme affects mitochondria, which is currently hard to reconcile mechanistically—although there are suggestions that parkin has a ubiquitin-independent function important for maintaining mitochondrial DNA integrity (see below).

    A second caveat about the PINK1-parkin relationship is that at face value there are two lipid membranes between the two proteins because PINK1 is in the mitochondrial matrix, whilst parkin is predominantly cytosolic. This does not diminish the impact of the current observations, but it needs to be resolved. One possible explanation is that PINK1 is not strictly mitochondrial, or parkin is not strictly cytosolic. There is experimental support for both possibilities. In transient transfections, with all the attendant caveats about overexpression and modification of proteins, some mature PINK1 ends up in the cytosol (Beilina et al., 2004). Parkin has been associated with the outer mitochondrial membrane (Darios et al., 2003) and more recently reported to be within mitochondria in proliferating cells, although not in quiescent cells such as neurons (Kuroda et al., 2006). Therefore, it is possible that the two proteins communicate by shuttling between mitochondria and cytoplasm. An alternative explanation is that a shared interactor or substrate of the two enzymes mediates the communication between the mitochondrion and the cytosol. Detailed studies of where the two proteins, and their substrates, are found in the brain of Drosophila and vertebrates are therefore warranted.


    . Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature. 2006 Jun 29;441(7097):1162-6. PubMed.

    . Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature. 2006 Jun 29;441(7097):1157-61. PubMed.

    . Early-onset familial parkinsonism due to POLG mutations. Ann Neurol. 2006 May;59(5):859-62. PubMed.

    . High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet. 2006 May;38(5):515-7. PubMed.

    . Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat Genet. 2006 May;38(5):518-20. PubMed.

    . Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability. Proc Natl Acad Sci U S A. 2005 Apr 19;102(16):5703-8. 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 enhances mitochondrial biogenesis in proliferating cells. Hum Mol Genet. 2006 Mar 15;15(6):883-95. PubMed.

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