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: 15.05). 11/2009; 64(3):328-40. DOI: 10.1016/j.neuron.2009.08.036
Source: PubMed


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.
    Full-text · Article · Oct 2012 · Molecular Biology and Evolution
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    • "HEK293T and SH-SY5Y cells were maintained in DMEM (Hyclone) supplemented with 10% FBS (Hyclone) and 1% penicillin/streptomycin. HEK cells stably expressing human APP Swedish mutations (HEK-APPSwe) were maintained in the same media with the addition of 400 μg/mL G418 (Invitrogen). Hela cells were maintained in RPMI-1640 (Hyclone) supplemented with 10% FBS and 1% penicillin/streptomycin. Maintenance of N2a cells stably expressing human APP695 (N2a-APP) was as previously reported [29]. Primary neurons derived from APP/PS1/tau triple transgenic mice collected at postnatal day 0 were cultured in Neurobasal medium supplemented with B-27 (Invitrogen). "
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    ABSTRACT: β-site APP cleaving enzyme 1 (BACE1) cleaves β-amyloid precursor protein (APP) to initiate the production of β-amyloid (Aβ), the prime culprit in Alzheimer's disease (AD). Dysregulation of the intracellular trafficking of BACE1 may affect Aβ generation, contributing to AD pathology. In this study, we investigated whether BACE1 trafficking and BACE1-mediated APP processing/Aβ generation are affected by sorting nexin 12 (SNX12), a member of the sorting nexin (SNX) family that is involved in protein trafficking regulation. Herein, we find that SNX12 is widely expressed in brain tissues and is mainly localized in the early endosomes. Overexpression of SNX12 does not affect the steady-state levels of APP, BACE1 or γ-secretase components, but dramatically reduces the levels of Aβ, soluble APPβ and APP β-carboxyl terminal fragments. Downregulation of SNX12 has the opposite effects. Modulation of SNX12 levels does not affect γ-secretase activity or in vitro β-secretase activity. Further studies reveal that SNX12 interacts with BACE1 and downregulation of SNX12 accelerates BACE1 endocytosis and decreases steady-state level of cell surface BACE1. Finally, we find that the SNX12 protein level is dramatically decreased in the brain of AD patients as compared to that of controls. This study demonstrates that SNX12 can regulate the endocytosis of BACE1 through their interaction, thereby affecting β-processing of APP for Aβ production. The reduced level of SNX12 in AD brains suggests that an alteration of SNX12 may contribute to AD pathology. Therefore, inhibition of BACE1-mediated β-processing of APP by regulating SNX12 might serve as an alternative strategy in developing an AD intervention.
    Full-text · Article · Jun 2012 · Molecular Neurodegeneration
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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.
    Preview · Article · Oct 2010 · Genome Research
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