Pink Mutations Link Parkinson’s Disease to Mitochondria

Mutations in Pink1, a gene coding for a mitochondrial protein kinase, has just been fingered as a genetic cause for parkinsonism. In today’s Sciencexpress, Nicholas Wood from the Institute of Neurology, London, together with a host of collaborators from the UK, Italy, Germany, the USA and Spain, report that Pink1 and PARK6, a long-sought-after genetic locus that is linked with early onset Parkinson’s disease, are one and the same.

Pink1 brings to five the total number of genes that are known to cause Parkinson’s disease or parkinsonism when mutated, the other four being α -synuclein, parkin, Uch-L1, and DJ-1. The last, once known as PARK7, was identified just over a year ago (see ARF related news story).

First author Enza Maria Valente and colleagues traced the origin of the PARK6 locus by mapping mutations in affected families from Sicily, central Italy, and Spain, homing in on a small region of chromosome 1. The authors then analyzed individual genes in the location. They found that affected members of the families had homozygous mutations in either of two loci, both in Pink1. Members of the Spanish family carried a simple guanine-to-adenine transition in exon 4 of the gene, while both Italian families were affected by a similar G-to-A transition in exon 7.

Pink1 is a 581 amino acid protein with a mitochondrial signal sequence. It has homology to serine/threonine kinases, which helps explain why the mutations are so devastating. When the authors compared Pink1 with other kinases, they found that the exon 4 mutation replaces a highly conserved glycine in the kinase domain with aspartic acid, while the exon 7 mutation, which results in premature termination of the protein, completely abolishes the C-terminus of the same domain.

But what does Pink1 do? It may be necessary to maintain the electrical balance across the mitochondrial membrane, suggest the authors. When Valente and colleagues stressed mitochondria expressing the exon 4 mutant, they found that the membrane potential decreased by 44 percent, whereas that of wild-type mitochondria fell by only 8 percent under the same conditions. They also found that wild-type Pink1 can protect cells against mitochondrial-induced apoptosis, whereas the mutant could not.

These findings add significantly to a growing body of literature on the role of mitochondria in Parkinson’s. While mitochondrial toxins are known to cause neurodegeneration and are widely used to mimic Parkinson’s in animal models, a direct link between these organelles and familial Parkinson’s disease has been lacking. Recently, it was shown that mutations in parkin can have global effects on mitochondrial protein expression and activity (see ARF related news story and ARF news story). The identification of Pink1 as a Parkinson’s gene will no doubt steel those who have been focusing on the mitochondrial connection. Incidentally, the same issue of Science magazine also carries a report on a mitochondrial enzyme that interacts specifically with Aβ, supporting the widely held assumption that an inability of mitochondria to handle cell stress may be a general but important factor that interacts with disease-specific molecules to cause Parkinson’s in one person and AD in another.—Tom Fagan

Comments

  1. The cloning of the gene for the PARK6 locus by Enza-Maria Valente and her colleagues now gives us a triumvirate of recessive genes that cause parkinsonism in humans; parkin, DJ-1 and now Pink1. Logically, the identification of three recessive mutations with similar phenotypes suggests that either 1) these three genes now delineate a single pathogenic pathway or 2) they point to different pathogenic processes that happen to all cause loss of a small group of neurons in the substantia nigra.

    PINK1 looks very much like a serine/threonine-directed protein kinase, and thus has no immediate connection to the E3-ligase activity of parkin or the varied putative activities of DJ-1. This suggests the involvement of diverse cellular pathways. However, there are one or two intersecting observations that may indicate some similarities among these different gene products. The first is that Pink1 localizes to mitochondria. DJ-1 can localize to mitochondria under some circumstances, and a fraction of parkin is also found in this organelle. The proportion of parkin that localizes to mitochondria is small, but experiments in mice and flies suggest that there are mitochondrial effects of parkin knockout. The other thing that links these three proteins is that all three protect cells against “stress” in a very broad sense. Thus, parkin protects against proteasome inhibition and mitochondrial stress, DJ-1 against oxidative events (which may be mitochondrial in nature) and proteasome inhibition, and Pink1 protects against proteasomal dysfunction and mitochondrial damage. Which leaves us with a number of important questions to answer. The mechanism by which Pink1 protects cells against mitochondrial damage secondary to proteasome inhibition is unclear and Valente et al. evoke a mitochondrial substrate. So what are the kinase substrates of Pink1? And is Pink1 somehow intertwined with parkin and DJ-1; or is the concept of one pathogenic cascade a red (or pink) herring?

    View all comments by Mark Cookson

  2. The two exciting reports in ScienceExpress of two discoveries, one, the mutant Pink1 gene at the root of PARK6-linked autosomal recessive Parkinson disease; and two, the functional inactivation of parkin's ubiquitin ligase activity by S-nitrosylation, provide strong support for an integrated picture of Parkinson's disease. The characterizations of Pink1 localization (and thus, likely, function) in mitochondria and parkin's inactivation as a result of excess oxidative stress cement two cornerstones of PD pathogenesis, mitochondrial impairment and sustained oxidative stress. They also highlight the relevance of wild-type parkin in the development of sporadic, late-onset PD, given its role in regulating steady-state levels of both mitochondrial enzymes and antioxidant proteins in parkin-deficient mouse brain (see Palacino et al., 2004 in ARF related news story).

    References:

    Palacino JJ, Sagi D, Goldberg MS, Krauss S, Motz C, Wacker M, Klose J, Shen J. Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem. 2004 Apr 30;279(18):18614-22. PubMed.

    View all comments by Michael Schlossmacher

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References

News Citations

  1. New Parkinson’s Gene: DJ Mutations Make Neurons Change Their Tune
  2. Loss of Parkin in Mammals Takes Steam Out of Mitochondria
  3. New Parkinson's Fly Can’t Fly, Implicating Mitochondria

Further Reading

Primary Papers

  1. Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, González-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science. 2004 May 21;304(5674):1158-60. Epub 2004 Apr 15 PubMed.

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