Function of saitohin, a novel protein that confers susceptibility to dementia

描述（由申请人提供）：Saitohin（一种赋予痴呆易感性的新蛋白质）的功能Saitohin（STH）是编码128个氨基酸的开放阅读框的基因，位于人tau基因的外显子9和10之间的内含子中。它与任何已知的蛋白质或基序没有明显的同源性，其表达模式与人类组织中的tau非常相似。STH仅存在于与人类关系最密切的灵长类动物（黑猩猩、倭黑猩猩和大猩猩）中并表达。已经鉴定了人STH的单一多态性，其将谷氨酰胺残基7改变为精氨酸（Q7 R）。这种多态性与两种tau基因单倍型相关：Q等位基因与H1相关，R等位基因与H2相关。Q等位基因是人类中最常见的单倍型，但所有非人灵长类动物的STH对于R等位基因是纯合的，这使得Q等位基因成为人类特异性标记。除了进化研究外，STHR等位基因似乎与阿尔茨海默病（AD）相关，特别是由ApoE 4易感因子引起的。相反，Q等位基因已被证明在几种神经退行性疾病中过度表达：进行性核上性麻痹（PSP），额颞叶痴呆（FTD）和帕金森病（PD）。这些结果表明，鉴定STH的功能可能涉及参与神经变性的几种蛋白质和/或途径。利用STH在酵母双杂交筛选中，我们确定过氧化物氧还蛋白6（Prdx 6）作为其配体之一。我们通过额外的测定证实了这种相互作用，并发现两个STH等位基因显示出与Prdx 6的差异相互作用。Prdx 6是一种独特的过氧化物氧还蛋白，具有所有家族成员共有的抗氧化功能和额外的磷脂酶活性。除了在正常细胞中的作用外，Prdx 6在皮克病（PiD）中升高，这是一种与PSP和FTD相关的疾病。此外，Prdx 6使tau去磷酸化，并且这种活性被STH等位基因之一增强。这些发现使我们形成了这样的假设，即STH通过其与Prdx 6的等位基因特异性相互作用影响tau功能。在这个探索性的补助金中，我们将测试这个理论。我们将研究两种Prdx 6功能中的哪一种受STH影响，以及STH/Prdx 6相互作用如何调节tau磷酸化（包括鉴定相互作用所需的每个分子的区域以及受这种相互作用影响的tau残基）。我们还将研究STH定位在哪里，两个STH等位基因如何影响不表达它们的细胞（P19小鼠畸胎瘤）以及STH抑制如何影响表达它们的细胞（SY 5 Y人神经母细胞瘤）-特别是：过程长度和延伸率; Prdx 6和选定的细胞骨架标记物的定位;内源性tau剪接，磷酸化和微管亲和力。一种新的痴呆易感蛋白--斋藤素的功能。这些研究将阐明STH的功能及其与正常脑功能和神经退行性变的关系。这也可能有助于解释我们这个物种对衰老的痛苦的独特易感性。

DESCRIPTION (provided by applicant): Function of saitohin, a novel protein that confers susceptibility to dementia Saitohin (STH), a gene encoding an open reading frame of 128 amino acids, is located in the intron between exons 9 and 10 of the human tau gene. It bears no obvious homology to any known protein or motif and its expression pattern is very similar to that of tau in human tissues. STH is present and expressed exclusively in the primates most closely related to humans (chimpanzee, bonobo and gorilla). A single polymorphism of human STH has been identified that changes glutamine residue 7 to arginine (Q7R). This polymorphism is associated with the two tau gene haplotypes: the Q allele with H1, the R allele with H2. The Q allele is the most common haplotype in humans but the STH of all nonhuman primates is homozygous for the R allele, which makes the Q allele a human-specific marker. In addition to evolution a study, the STH R allele seems to be associated with Alzheimer's disease (AD) specifically resulting from the ApoE4 susceptibility factor. Conversely, the Q allele has been shown to be over-represented in several neurodegenerative diseases: progressive supranuclear palsy (PSP), frontotemporal dementia (FTD) and Parkinson's disease (PD). These results suggest that identifying a function of STH could implicate several proteins and/or pathways involved in neurodegeneration. Using STH in a yeast two-hybrid screening, we identified Peroxiredoxin 6 (Prdx6) as one of its ligands. We confirmed this interaction by additional assays and discovered that the two STH alleles show differential interactions with Prdx6. Prdx6 is a unique peroxiredoxin that has the antioxidant function common to all the family members and an additional phospholipase activity. Besides its role in normal cells, Prdx6 is elevated in Pick's disease (PiD), a disorder related to PSP and FTD. Additionally, Prdx6 dephosphorylates tau and this activity is enhanced by one of the STH alleles. These findings led us to form the hypothesis that STH influences tau function through its allele-specific interaction with Prdx6. In this exploratory grant, we will test this theory. We will investigate which of the two Prdx6 functions is influenced by STH, and how the STH/Prdx6 interaction modulates tau phosphorylation (including identification of the regions of each molecule required for interaction and of the tau residue(s) affected by this interaction). We will also examine where STH localizes, how the two STH alleles influence cells which do not express them (P19 mouse teratocarcinoma) and how STH suppression influences cells which express them (SY5Y human neuroblastoma) - specifically: process length and extension rate; localization of Prdx6 and selected cytoskeletal markers; endogenous tau splicing, phosphorylation and microtubule affinity. Function of saitohin, a novel protein that confers susceptibility to dementia. These studies will clarify the function(s) of STH and its connection to normal brain function and neurodegeneration. It may also help explain the unique susceptibility of our species to the woes of senility.