Scheper Wiep, Zwart Rob, Baas Frank
Neurogenetics Laboratory, Academic Medical Center, Amsterdam, The Netherlands.
Neurogenetics. 2004 Dec;5(4):223-7. doi: 10.1007/s10048-004-0195-y. Epub 2004 Oct 5.
Presenilin 1 (PS1) is mutated in the majority of familial cases of Alzheimer disease (AD). Although it is clear that PS1 is involved in the processing of the amyloid precursor protein (APP), the exact function of PS1 is still elusive. Human presenilin 1 (PS1) is alternatively spliced, resulting in the presence or absence of a four-amino acid motif, VRSQ, in the PS1 N-terminus. In human tissues, both isoforms are expressed. Here we report that mouse and rat only express the longer PS1 isoform. The presence of this motif introduces a potential phosphorylation site for protein kinase C. Because the splice occurs in the region of PS1 that we have previously shown to bind to rabGDI, this might provide a regulatory mechanism for this interaction. Our data show that the -VRSQ isoform binds rabGDI, but the +VRSQ does not. Moreover, mutation of the putatively phosphorylated threonine in PS1 disrupts the binding to rabGDI, showing its importance for the interaction. To our knowledge this is the first study showing a functional difference between PS1 splice variants. The possible consequences for APP processing and the pathogenesis of AD are discussed.
早老素1（PS1）在大多数家族性阿尔茨海默病（AD）病例中发生突变。虽然很明显PS1参与淀粉样前体蛋白（APP）的加工，但PS1的确切功能仍然难以捉摸。人类早老素1（PS1）存在可变剪接，导致PS1 N端存在或不存在一个四氨基酸基序VRSQ。在人体组织中，两种异构体均有表达。在此我们报告，小鼠和大鼠只表达较长的PS1异构体。这个基序的存在引入了一个蛋白激酶C的潜在磷酸化位点。由于剪接发生在我们之前已证明能与rabGDI结合的PS1区域，这可能为这种相互作用提供一种调节机制。我们的数据表明，-VRSQ异构体与rabGDI结合，而+VRSQ则不结合。此外，PS1中假定磷酸化的苏氨酸发生突变会破坏与rabGDI的结合，表明其对这种相互作用的重要性。据我们所知，这是第一项显示PS1剪接变体之间功能差异的研究。文中还讨论了其对APP加工及AD发病机制可能产生的影响。
