A Functional Mouse Retroposed Gene Rps23r1 Reduces Alzheimer's β-Amyloid Levels and Tau Phosphorylation

Institute for Biomedical Research, Xiamen University, Xiamen, China.
Neuron (Impact Factor: 15.98). 11/2009; 64(3):328-40. DOI: 10.1016/j.neuron.2009.08.036
Source: PubMed

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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    • "Some of these differences are of a high importance in medical research and may be responsible for the fact that results from animal studies cannot be transferred to humans. For example, the functional mouse retrogene Rps23r1 reduces Alzheimer's beta-amyloid levels and tau phosphorylation (Zhang et al. 2009). However, results of this study cannot be applied to humans because this particular retrogene is rodent specific and does not exist in the human genome. "
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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; 30(2). DOI:10.1093/molbev/mss235 · 14.31 Impact Factor
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    • "An example is a mouse retrocopy of a ribosomal protein gene (Rps23), of which there are hundreds in mammalian genomes and that usually represent nonfunctional retropseudogenes, consistent with the idea that duplication of these genes is usually redundant and/or is subject to dosage balance constraints. Yet the Rps23 retrocopy evolved a completely new function, not by changes in the protein-coding sequence, but by being transcribed from the reverse strand and the incorporation of sequences flanking its insertion site as new (coding and noncoding ) exons (Zhang et al. 2009). This gave rise to a new protein (completely unrelated to that encoded by its parental gene), which had profound functional implications in that it conferred increased resistance in mice against the formation of Alzheimercausing amyloid plaques. "
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    ABSTRACT: Ever since the pre-molecular era, the birth of new genes with novel functions has been considered to be a major contributor to adaptive evolutionary innovation. Here, I review the origin and evolution of new genes and their functions in eukaryotes, an area of research that has made rapid progress in the past decade thanks to the genomics revolution. Indeed, recent work has provided initial whole-genome views of the different types of new genes for a large number of different organisms. The array of mechanisms underlying the origin of new genes is compelling, extending way beyond the traditionally well-studied source of gene duplication. Thus, it was shown that novel genes also regularly arose from messenger RNAs of ancestral genes, protein-coding genes metamorphosed into new RNA genes, genomic parasites were co-opted as new genes, and that both protein and RNA genes were composed from scratch (i.e., from previously nonfunctional sequences). These mechanisms then also contributed to the formation of numerous novel chimeric gene structures. Detailed functional investigations uncovered different evolutionary pathways that led to the emergence of novel functions from these newly minted sequences and, with respect to animals, attributed a potentially important role to one specific tissue--the testis--in the process of gene birth. Remarkably, these studies also demonstrated that novel genes of the various types significantly impacted the evolution of cellular, physiological, morphological, behavioral, and reproductive phenotypic traits. Consequently, it is now firmly established that new genes have indeed been major contributors to the origin of adaptive evolutionary novelties.
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    ABSTRACT: Glycogen synthase kinase (GSK)-3 has been proposed as the link between the two histopathological hallmarks of Alzheimer's disease, the extracellular senile plaques composed of beta-amyloid and the intracellular neurofibrillary tangles formed from hyperphosphorylated tau. Thus, GSK-3 is one of the main tau kinases and it modifies several sites of the tau protein present in neurofibrillary tangles. Furthermore, GSK-3 is able to modulate the generation of amyloid-beta, as well as to respond to this peptide. In several transgenic models, overexpression of GSK-3 has been associated with neuronal death, tau hyperphosphorylation and a decline in cognitive performance. Lithium, a widely used drug for affective disorders, inhibits GSK-3 at therapeutically relevant concentrations and it has been demonstrated that this is able to prevent tau phosphorylation. In the present review, we summarize all these data and discuss the potential of GSK-3 inhibitors for Alzheimer's disease therapy, as well as some of their potential problems.
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