A functional mouse retroposed gene Rps23r1 reduces Alzheimer's beta-amyloid levels and tau phosphorylation.
ABSTRACT Senile plaques consisting of beta-amyloid (Abeta) and neurofibrillary tangles composed of hyperphosphorylated tau are major pathological hallmarks of Alzheimer's disease (AD). Elucidation of factors that modulate Abeta generation and tau hyperphosphorylation is crucial for AD intervention. Here, we identify a mouse gene Rps23r1 that originated through retroposition of ribosomal protein S23. We demonstrate that RPS23R1 protein reduces the levels of Abeta and tau phosphorylation by interacting with adenylate cyclases to activate cAMP/PKA and thus inhibit GSK-3 activity. The function of Rps23r1 is demonstrated in cells of various species including human, and in transgenic mice overexpressing RPS23R1. Furthermore, the AD-like pathologies of triple transgenic AD mice were improved and levels of synaptic maker proteins increased after crossing them with Rps23r1 transgenic mice. Our studies reveal a new target/pathway for regulating AD pathologies and uncover a retrogene and its role in regulating protein kinase pathways.
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ABSTRACT: Gene duplicates generated via retroposition were long thought to be pseudogenized and consequently decayed. However, a significant number of these genes escaped their evolutionary destiny and evolved into functional genes. Despite multiple studies, the number of functional retrogenes in human and other genomes remains unclear. We performed a comparative analysis of human, chicken, and worm genomes in order to identify "orphan" retrogenes, i.e. retrogenes that have replaced their progenitors. We located twenty five such candidates in the human genome. All of these genes were previously known and majority has been intensively studied. Despite this, they were never been recognized as retrogenes. Analysis revealed that the phenomenon of replacing parental genes by their retrocopies has been taking place over the entire span of animal evolution. This process was often species-specific and contributed to interspecies differences. Surprisingly, these retrogenes, which should evolve in a more relaxed mode, are subject to a very strong purifying selection, which is on average, two and a half times stronger than other human genes. Also, for retrogenes, they do not show a typical overall tendency for a testis specific expression. Notably, seven of them are associated with human diseases. Recognizing them as "orphan" retrocopies, which have different regulatory machinery than their parents, is important for any disease studies in model organisms, especially when discoveries made in one species are transferred to humans.Molecular Biology and Evolution 10/2012; · 14.31 Impact Factor
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ABSTRACT: Analysis of the human genome suggests novel genes created by retroposition may play an important role in primate evolution. However, data from non-human primates is still scarce. A comprehensive comparison was thus performed among four primate genomes (human, chimpanzee, orangutan, and macaque), which detects elevated rates of retroposition in both the common ancestor of hominoids and macaques. Further analysis shows approximately 10% of intact retrocopies may be under positive selection and at least 4% of retrocopies become functional copies eventually. Moreover, human intact retrocopies were found enriched in transcription-related functions. Collectively, these findings emphasize the important contribution of retroposition to primate genome evolution.FEBS letters 09/2013; · 3.54 Impact Factor