近日,，英國皇家學會《開放生物學》（Open Biology）雜志發(fā)表帕金森癥研究新發(fā)現(xiàn),，該成果向發(fā)現(xiàn)帕金森癥病因又邁進了一步。
英國帕金森癥患者近12萬人,，病因研究方面始終未獲突破進展,，目前仍沒有治療方法。雖然科學家已發(fā)現(xiàn)為PINK1蛋白合成指定密碼的某個基因的突變導致了帕金森癥,，但仍不清楚該基因突變是如何引起病變的,。
此次研究的突破在于科學家首次發(fā)現(xiàn)了測量PINK1活動的方法,?？茖W家發(fā)現(xiàn)病變導致PINK1不能正常工作，而PINK1的功能對于神經(jīng)原的存活十分重要,，由此可進一步鎖定發(fā)現(xiàn)帕金森癥病因的新目標,。(生物谷 Bioon.com)
doi:10.1016/10.1098/rsob.110012
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Discovery of catalytically active orthologues of the Parkinson's disease kinase PINK1: analysis of substrate specificity and impact of mutations
Helen I. Woodroof,, Joe H. Pogson, Mike Begley, Lewis C. Cantley, Maria Deak, David G. Campbell, Daan M. F. van Aalten, Alexander J. Whitworth, Dario R. Alessi and Miratul M. K. Muqit
Missense mutations of the phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) gene cause autosomal-recessive Parkinson's disease. To date, little is known about the intrinsic catalytic properties of PINK1 since the human enzyme displays such low kinase activity in vitro. We have discovered that, in contrast to mammalian PINK1, insect orthologues of PINK1 we have investigated—namely Drosophila melanogaster (dPINK1), Tribolium castaneum (TcPINK1) and Pediculus humanus corporis (PhcPINK1)—are active as judged by their ability to phosphorylate the generic substrate myelin basic protein. We have exploited the most active orthologue, TcPINK1, to assess its substrate specificity and elaborated a peptide substrate (PINKtide, KKWIpYRRSPRRR) that can be employed to quantify PINK1 kinase activity. Analysis of PINKtide variants reveal that PINK1 phosphorylates serine or threonine, but not tyrosine, and we show that PINK1 exhibits a preference for a proline at the +1 position relative to the phosphorylation site. We have also, for the first time, been able to investigate the effect of Parkinson's disease-associated PINK1 missense mutations, and found that nearly all those located within the kinase domain, as well as the C-terminal non-catalytic region, markedly suppress kinase activity. This emphasizes the crucial importance of PINK1 kinase activity in preventing the development of Parkinson's disease. Our findings will aid future studies aimed at understanding how the activity of PINK1 is regulated and the identification of physiological substrates.
