Beilina A, Van Der Brug M, Ahmad R, Kesavapany S, Miller DW, Petsko GA, Cookson MR. 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.

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  1. This paper by Mark Cookson’s group is very exciting: While it starts answering some of the numerous issues regarding PINK1 function, at the same time it poses new, intriguing questions. There are at least two important messages in this paper. First, the authors showed that at least one of the mutations—L347P— dramatically decreased the stability of PINK1 protein and its kinase activity. Kinase activity is also reduced for the stable G309D mutant, although in a less significant way. This demonstrates for the first time that PINK1 mutations act with a loss-of-function mechanism and that kinase activity of PINK1 is crucial to its function. The recent identification of another PD gene encoding a protein—dardarin—with likely kinase activity makes these findings even more interesting. Secondly, by expressing the protein with a variety of C-terminus tags in addition to those at the N-terminus, Beilina and co-workers clearly showed that PINK1 is processed in the mitochondria to a mature form about 8-10 kD smaller than the native protein, and that this mature form is enriched in the mitochondrial fraction after subcellular fractionation. These data show the cleavage of the predicted mitochondrial leading peptide at the N-terminus and indeed confirm the mitochondrial targeting of PINK1. But that’s not all, and some of the data presented in this work raise new, interesting queries. For instance, a consistent proportion of the mature PINK1 protein seems to localize in the cytosol. Although this could simply represent an artifact of protein overexpression, it is worth noting that cytoplasmic localization is not observed for N-terminus tagged PINK1, which represents the preprotein prior to mitochondrial cleavage. The authors suggest that, after processing of the leader peptide, a proportion of mature PINK1 could be exported back into the cytoplasm. This challenging hypothesis implies that mitochondria might not be the only scenario of action for PINK1.
    The cloning of PINK1, encoding the first mitochondrial protein directly linked to Parkinson disease, seemed to crown a large amount of evidence that pointed at mitochondrial dysfunction as the key pathogenetic event of PD, such as the mitochondrial effects observed in parkin knockout animal and cellular models, and the demonstration of mitochondrial relocalization of DJ-1 after oxidative stress. Now, should the cytoplasmic localization of a pool of mature PINK1 be confirmed for the endogenous protein, we will face a more complex scenario where the pathogenetic pathways of distinct PD genes can variably intersect at different cellular levels. At present, the understanding of this intricate interplay is one of the most thrilling challenges of PD research.

    View all comments by Enza Maria Valente

  2. Might we expect that the anti-inflammatory PPAR-γ agonists which upregulate PTEN may be especially beneficial for those with PINK1-PTEN-induced putative kinase 1 mutations?

    References:

    Lee KS, Park SJ, Hwang PH, Yi HK, Song CH, Chai OH, Kim JS, Lee MK, Lee YC. PPAR-gamma modulates allergic inflammation through up-regulation of PTEN. FASEB J. 2005 Jun;19(8):1033-5. PubMed.

    Patel L, Pass I, Coxon P, Downes CP, Smith SA, Macphee CH. Tumor suppressor and anti-inflammatory actions of PPARgamma agonists are mediated via upregulation of PTEN. Curr Biol. 2001 May 15;11(10):764-8. PubMed.

    View all comments by Mary Reid

  3. Of further interest is the finding by Kim et al. that DJ-1 is a regulator of PTEN.

    References:

    Kim RH, Peters M, Jang Y, Shi W, Pintilie M, Fletcher GC, DeLuca C, Liepa J, Zhou L, Snow B, Binari RC, Manoukian AS, Bray MR, Liu FF, Tsao MS, Mak TW. DJ-1, a novel regulator of the tumor suppressor PTEN. Cancer Cell. 2005 Mar;7(3):263-73. PubMed.

    View all comments by Mary Reid

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