Expression of tiRNA and tRF in APP/PS1 transgenic mice and the change of related proteins expression

Background Transcriptomics, such as that of non-coding RNA (ncRNA), which include microRNA (miRNA), circular RNA, and the transfer RNA (tRNA)-derived fragments (tiRNA and tRF) in Alzheimer’s disease (AD) have attracted much attention recently. The tiRNA and tRFs are produced when the tRNA splits at specific sites. The expression change and related function of tiRNA and tRFs in AD has not been fully investigated. Methods In our study, APP/PS1 transgenic mice (AD mice model) and healthy control mice were used to discover the differentially expressed tiRNA and tRFs with high-throughput sequencing. Among the differentially expressed tiRNA and tRFs, we chose two tRFs (tRF-Thr-CGT-003 and tRF-Leu-CAA-004) and predicted the target messenger RNAs (mRNAs) with miRanda and Target Scan. The target mRNAs of tRF-related function and pathways were analyzed, then we performed quantitative reverse transcription polymerase chain reaction (RT-qPCR) and western blot to validate the related target mRNAs and pathways. Results A total of 27 significantly different tiRNA and tRFs were detected between wild type (WT) and APP/PS1 groups, including 14 up-regulated and 13 down-regulated. Through analyzing the target mRNAs of all differentially expressed tiRNA and tRFs with GO enrichment, we found the target mRNAs could take part in the learning and memory biological process, synapse organization, cognition biological process, synaptic transmission, amyloid-β (Aβ) metabolic process, and so on. We then chose three differentially expressed tRFs for further qPCR validation and passed two tRFs: tRF-Thr-CGT-003 and tRF-Leu-CAA-004, that were found to regulate the calcium regulation-related proteins (the voltage-gated calcium channel γ2 subunit and the RYR1 endoplasmic reticulum calcium released protein) and the retinol metabolism-related proteins (retinoic acid metabolic enzymes CYP2S1, CYP2C68, CYP2S1). Conclusions The APP expression and presenilin mutation in APP/PS1 mice could cause tiRNA and tRFs expression change. Among the differentially expressed tiRNA and tRFs, we found some tRFs took part in the voltage-gated calcium channel γ2 subunit expression and regulation, influencing the neuron calcium homeostasis. Moreover, we also found the tRFs may participate in the regulation of retinol metabolism. Our findings suggest that the dysregulated tiRNA and tRFs may be beneficially exploited as potential diagnostic biomarkers and/or therapeutic targets of AD.

[1]  Feng Yan,et al.  tRNA-Derived Fragment tRF-17-79MP9PP Attenuates Cell Invasion and Migration via THBS1/TGF-β1/Smad3 Axis in Breast Cancer , 2021, Frontiers in Oncology.

[2]  Inhan Lee,et al.  tRNA-Derived Fragments in Alzheimer's Disease: Implications for New Disease Biomarkers and Neuropathological Mechanisms. , 2020, Journal of Alzheimer's disease : JAD.

[3]  B. Bacskai,et al.  Therapeutic Strategies to Target Calcium Dysregulation in Alzheimer’s Disease , 2020, Cells.

[4]  A. Gorji,et al.  MicroRNA alterations in neuropathologic cognitive disorders with an emphasis on dementia: Lessons from animal models , 2020, Journal of cellular physiology.

[5]  J. Prehn,et al.  Angiogenin and tRNA fragments in Parkinson’s disease and neurodegeneration , 2020, Acta Pharmacologica Sinica.

[6]  Yonghe Li,et al.  Restoring Wnt/β-catenin signaling is a promising therapeutic strategy for Alzheimer’s disease , 2019, Molecular Brain.

[7]  Shuai Zhang,et al.  Identification of functional tRNA-derived fragments in senescence-accelerated mouse prone 8 brain , 2019, Aging.

[8]  A. Múnera,et al.  Bexarotene therapy ameliorates behavioral deficits and induces functional and molecular changes in very-old Triple Transgenic Mice model of Alzheimer´s disease , 2019, PloS one.

[9]  D. Praticò,et al.  Impaired mitochondrial calcium efflux contributes to disease progression in models of Alzheimer’s disease , 2019, Nature Communications.

[10]  P. Reddy,et al.  Dynamics of Dynamin-Related Protein 1 in Alzheimer’s Disease and Other Neurodegenerative Diseases , 2019, Cells.

[11]  B. Li,et al.  A tRNA fragment, 5'-tiRNAVal, suppresses the Wnt/β-catenin signaling pathway by targeting FZD3 in breast cancer. , 2019, Cancer letters.

[12]  G. Duester,et al.  Retinoic acid signaling pathways , 2019, Development.

[13]  M. Nair,et al.  Alzheimer’s disease: pathogenesis, diagnostics, and therapeutics , 2019, International journal of nanomedicine.

[14]  Junming Guo,et al.  tRNA-derived fragments and tRNA halves: The new players in cancers. , 2019, Cancer letters.

[15]  S. Lovestone,et al.  Genetic and Real-World Clinical Data, Combined with Empirical Validation, Nominate Jak-Stat Signaling as a Target for Alzheimer’s Disease Therapeutic Development , 2019, Cells.

[16]  Ji-zong Zhao,et al.  Expression analysis of transfer RNA-derived fragments in the blood of patients with moyamoya disease: A preliminary study , 2019, Molecular medicine reports.

[17]  Wei Zheng,et al.  Ca2+ homeostasis dysregulation in Alzheimer's disease: a focus on plasma membrane and cell organelles , 2019, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[18]  L. Goldstein,et al.  Cholesterol Metabolism Is a Druggable Axis that Independently Regulates Tau and Amyloid-β in iPSC-Derived Alzheimer’s Disease Neurons , 2019, Cell stem cell.

[19]  É. Kiss,et al.  Early alterations in hippocampal perisomatic GABAergic synapses and network oscillations in a mouse model of Alzheimer’s disease amyloidosis , 2019, PloS one.

[20]  N. Polacek,et al.  A tRNA half modulates translation as stress response in Trypanosoma brucei , 2019, Nature Communications.

[21]  Junming Guo,et al.  Transfer RNA-derived fragments and tRNA halves: biogenesis, biological functions and their roles in diseases , 2018, Journal of Molecular Medicine.

[22]  Anindya Dutta,et al.  tRNA fragments (tRFs) guide Ago to regulate gene expression post-transcriptionally in a Dicer-independent manner , 2018, RNA.

[23]  J. Sheng,et al.  tRNA-Derived Small RNA: A Novel Regulatory Small Non-Coding RNA , 2018, Genes.

[24]  Kotb Abdelmohsen,et al.  Noncoding RNAs in Alzheimer's disease , 2018, Wiley interdisciplinary reviews. RNA.

[25]  Yongmei Yin,et al.  Roles of tRNA-derived fragments in human cancers. , 2018, Cancer letters.

[26]  S. Kuerten,et al.  Danger: High Voltage—The Role of Voltage-Gated Calcium Channels in Central Nervous System Pathology , 2017, Cells.

[27]  Michael W. Weiner,et al.  Metabolic network failures in Alzheimer's disease: A biochemical road map , 2017, Alzheimer's & Dementia.

[28]  P. Passmore,et al.  Serum concentrations of vitamin E and carotenoids are altered in Alzheimer's disease: A case-control study , 2017, Alzheimer's & dementia.

[29]  Zesong Li,et al.  tRF/miR-1280 Suppresses Stem Cell-like Cells and Metastasis in Colorectal Cancer. , 2017, Cancer research.

[30]  A. Hannan,et al.  Exercise alters mouse sperm small noncoding RNAs and induces a transgenerational modification of male offspring conditioned fear and anxiety , 2017, Translational Psychiatry.

[31]  E. Schon,et al.  On the Pathogenesis of Alzheimer's Disease: The MAM Hypothesis , 2017, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[32]  Z. Khachaturian,et al.  Calcium Hypothesis of Alzheimer's disease and brain aging: A framework for integrating new evidence into a comprehensive theory of pathogenesis , 2017, Alzheimer's & Dementia.

[33]  C. Mammucari,et al.  Calcium at the Center of Cell Signaling: Interplay between Endoplasmic Reticulum, Mitochondria, and Lysosomes. , 2016, Trends in biochemical sciences.

[34]  P. Ivanov,et al.  YB-1 regulates tiRNA-induced Stress Granule formation but not translational repression , 2016, Nucleic acids research.

[35]  Patricia P. Chan,et al.  tRNAscan-SE On-line: integrating search and context for analysis of transfer RNA genes , 2016, Nucleic Acids Res..

[36]  G. Ullah,et al.  Impaired mitochondrial function due to familial Alzheimer's disease-causing presenilins mutants via Ca(2+) disruptions. , 2016, Cell calcium.

[37]  Xin Niu,et al.  tRNA-Derived Small Non-Coding RNAs in Response to Ischemia Inhibit Angiogenesis , 2016, Scientific Reports.

[38]  Oliver J. Rando,et al.  Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals , 2016, Science.

[39]  Xudong Zhang,et al.  Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder , 2016, Science.

[40]  Xiaoyong Bao,et al.  Respiratory Syncytial Virus Utilizes a tRNA Fragment to Suppress Antiviral Responses Through a Novel Targeting Mechanism. , 2015, Molecular therapy : the journal of the American Society of Gene Therapy.

[41]  K. Swanson,et al.  Age-driven modulation of tRNA-derived fragments in Drosophila and their potential targets , 2015, Biology Direct.

[42]  Lisa Fish,et al.  Endogenous tRNA-Derived Fragments Suppress Breast Cancer Progression via YBX1 Displacement , 2015, Cell.

[43]  E. Choi,et al.  Compromised MAPK signaling in human diseases: an update , 2015, Archives of Toxicology.

[44]  Pavel Ivanov,et al.  tRNA fragments in human health and disease , 2014, FEBS letters.

[45]  Suresh B. Mudunuri,et al.  Meta-analysis of tRNA derived RNA fragments reveals that they are evolutionarily conserved and associate with AGO proteins to recognize specific RNA targets , 2014, BMC Biology.

[46]  E. Schon,et al.  Mitochondria-associated ER membranes in Alzheimer disease , 2013, Molecular and Cellular Neuroscience.

[47]  U. Lerner,et al.  Vitamin a metabolism, action, and role in skeletal homeostasis. , 2013, Endocrine reviews.

[48]  G. Hutvagner,et al.  Small RNAs derived from the 5′ end of tRNA can inhibit protein translation in human cells , 2013, RNA biology.

[49]  C. Hobbs,et al.  Amyloid β inhibits retinoic acid synthesis exacerbating Alzheimer disease pathology which can be attenuated by an retinoic acid receptor α agonist , 2013, The European journal of neuroscience.

[50]  S. S. Ajay,et al.  Identification and functional characterization of tRNA-derived RNA fragments (tRFs) in respiratory syncytial virus infection. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[51]  N. Polacek,et al.  tRNA-Derived Fragments Target the Ribosome and Function as Regulatory Non-Coding RNA in Haloferax volcanii , 2012, Archaea.

[52]  T. Speed,et al.  A Tetrahymena Piwi bound to mature tRNA 3' fragments activates the exonuclease Xrn2 for RNA processing in the nucleus. , 2012, Molecular cell.

[53]  T. Casoli,et al.  Early impairment of long-term depression in the perirhinal cortex of a mouse model of Alzheimer's disease. , 2012, Rejuvenation research.

[54]  D. Corey,et al.  Argonaute and the nuclear RNAs: new pathways for RNA-mediated control of gene expression. , 2012, Nucleic acid therapeutics.

[55]  Steven P Gygi,et al.  Angiogenin-induced tRNA fragments inhibit translation initiation. , 2011, Molecular cell.

[56]  D. Small,et al.  Amyloid-beta decreases cell-surface AMPA receptors by increasing intracellular calcium and phosphorylation of GluR2. , 2010, Journal of Alzheimer's disease : JAD.

[57]  Pavel Ivanov,et al.  Angiogenin-induced tRNA-derived Stress-induced RNAs Promote Stress-induced Stress Granule Assembly* , 2010, The Journal of Biological Chemistry.

[58]  Davis J. McCarthy,et al.  edgeR: a Bioconductor package for differential expression analysis of digital gene expression data , 2009, Bioinform..

[59]  M. Nashimoto,et al.  Human cytosolic tRNase ZL can downregulate gene expression through miRNA , 2009, FEBS letters.

[60]  S. Le,et al.  Pyrosequencing of small non-coding RNAs in HIV-1 infected cells: evidence for the processing of a viral-cellular double-stranded RNA hybrid , 2009, Nucleic acids research.

[61]  Ivan V. Goussakov,et al.  Deviant Ryanodine Receptor-Mediated Calcium Release Resets Synaptic Homeostasis in Presymptomatic 3xTg-AD Mice , 2009, The Journal of Neuroscience.

[62]  Cole Trapnell,et al.  Ultrafast and memory-efficient alignment of short DNA sequences to the human genome , 2009, Genome Biology.

[63]  J. Hell.  Faculty Opinions recommendation of The stargazin-related protein gamma 7 interacts with the mRNA-binding protein heterogeneous nuclear ribonucleoprotein A2 and regulates the stability of specific mRNAs, including CaV2.2. , 2008 .

[64]  M. Block,et al.  Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model , 2008, The Journal of Neuroscience.

[65]  Patricia P. Chan,et al.  GtRNAdb: a database of transfer RNA genes detected in genomic sequence , 2008, Nucleic Acids Res..

[66]  R. Nicoll,et al.  TARP Subtypes Differentially and Dose-Dependently Control Synaptic AMPA Receptor Gating , 2007, Neuron.

[67]  Olivier Thibault,et al.  Expansion of the calcium hypothesis of brain aging and Alzheimer's disease: minding the store , 2007, Aging cell.

[68]  Aaron M. Beedle,et al.  Inhibition of Recombinant N-Type CaV Channels by the γ2 Subunit Involves Unfolded Protein Response (UPR)-Dependent and UPR-Independent Mechanisms , 2007, The Journal of Neuroscience.

[69]  P. Mecocci,et al.  Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer’s disease , 2003, Neurobiology of Aging.

[70]  K. Campbell,et al.  Auxiliary subunits: essential components of the voltage-gated calcium channel complex , 2003, Current Opinion in Neurobiology.

[71]  A. Pardee,et al.  Evidence for defective retinoid transport and function in late onset Alzheimer's disease , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[72]  H. Man,et al.  Amyloid-β Induces AMPA Receptor Ubiquitination and Degradation in Primary Neurons and Human Brains of Alzheimer's Disease. , 2018, Journal of Alzheimer's disease : JAD.

[73]  J. Güell-Bosch,et al.  Mouse Models of Alzheimer's Disease. , 2017, Journal of Alzheimer's disease : JAD.

[74]  W. Hammerstein,et al.  Pathogenesis , 1869, The Chicago Medical Journal.

[75]  A. Takashima,et al.  Vitamin A has anti-oligomerization effects on amyloid-β in vitro. , 2011, Journal of Alzheimer's disease : JAD.

[76]  D. Selkoe.  Alzheimer's disease. , 2011, Cold Spring Harbor perspectives in biology.

[77]  Z. Sellers,et al.  Calcium channel gamma subunits: a functionally diverse protein family. , 2007, Cell biochemistry and biophysics.

[78]  W. Gong,et al.  TGF-beta1 disrupts endotoxin signaling in microglial cells through Smad3 and MAPK pathways. , 2004, Journal of immunology.

[79]  N. Klugbauer,et al.  Calcium channel alpha2delta subunits: differential expression, function, and drug binding. , 2003, Journal of bioenergetics and biomembranes.

[80]  K. Campbell,et al.  Gamma subunit of voltage-activated calcium channels. , 2003, The Journal of biological chemistry.