Browsing by Author "Wang, Ruizhi"

Now showing 1 - 7 of 7
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    APPealing for a role in cellular iron efflux
    (American Society for Biochemistry and Molecular Biology, 2019-06-14) Lahiri, Debomoy K.; Maloney, Bryan; Wang, Ruizhi; Medical and Molecular Genetics, School of Medicine
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    Effects of microRNA-298 on APP and BACE1 translation differ according to cell type and 3′-UTR variation
    (Springer, 2022-02-23) Wang, Ruizhi; Lahiri, Debomoy K.; Psychiatry, School of Medicine
    Alzheimer’s disease (AD) is marked by neurofibrillary tangles and senile plaques composed of amyloid β (Aβ) peptides. However, specific contributions of different cell types to Aβ deposition remain unknown. Non-coding microRNAs (miRNA) play important roles in AD by regulating translation of major associated proteins, such as Aβ precursor protein (APP) and β-site APP-cleaving enzyme (BACE1), two key proteins associated with Aβ biogenesis. MiRNAs typically silence protein expression via binding specific sites in mRNAs’ 3′-untranslated regions (3′-UTR). MiRNAs regulate protein levels in a cell-type specific manner; however, mechanisms of the variation of miRNA activity remain unknown. We report that miR-298 treatment reduced native APP and BACE1 protein levels in an astrocytic but not in a neuron-like cell line. From miR-298’s effects on APP-3′-UTR activity and native protein levels, we infer that differences in APP 3′-UTR length could explain differential miR-298 activity. Such varied or truncated, but natural, 3′-UTR specific to a given cell type provides an opportunity to regulate native protein levels by particular miRNA. Thus, miRNA’s effect tailoring to a specific cell type, bypassing another undesired cell type with a truncated 3′-UTR would potentially advance clinically-relevant translational research.
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    How autism and Alzheimer’s disease are TrAPPed
    (Springer Nature, 2021) Lahiri, Debomoy K.; Maloney, Bryan; Wang, Ruizhi; Sokol, Deborah K.; Rogers, Jack T.; Westmark, Cara J.; Psychiatry, School of Medicine
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    Human microRNA (miR-20b-5p) modulates Alzheimer's disease pathways and neuronal function, and a specific polymorphism close to the MIR20B gene influences Alzheimer's biomarkers
    (Springer Nature, 2022) Wang, Ruizhi; Chopra, Nipun; Nho, Kwangsik; Maloney, Bryan; Obukhov, Alexander G.; Nelson, Peter T.; Counts, Scott E.; Lahiri, Debomoy K.; Psychiatry, School of Medicine
    Alzheimer's disease (AD) is a progressive neurodegenerative disorder with loss of cognitive, executive, and other mental functions, and is the most common form of age-related dementia. Amyloid-β peptide (Aβ) contributes to the etiology and progression of the disease. Aβ is derived from the amyloid-β precursor protein (APP). Multiple microRNA (miRNA) species are also implicated in AD. We report that human hsa-miR20b-5p (miR-20b), produced from the MIR20B gene on Chromosome X, may play complex roles in AD pathogenesis, including Aβ regulation. Specifically, miR-20b-5p miRNA levels were altered in association with disease progression in three regions of the human brain: temporal neocortex, cerebellum, and posterior cingulate cortex. In cultured human neuronal cells, miR-20b-5p treatment interfered with calcium homeostasis, neurite outgrowth, and branchpoints. A single-nucleotide polymorphism (SNP) upstream of the MIR20B gene (rs13897515) associated with differences in levels of cerebrospinal fluid (CSF) Aβ1-42 and thickness of the entorhinal cortex. We located a miR-20b-5p binding site in the APP mRNA 3'-untranslated region (UTR), and treatment with miR-20b-5p reduced APP mRNA and protein levels. Network analysis of protein-protein interactions and gene coexpression revealed other important potential miR-20b-5p targets among AD-related proteins/genes. MiR-20b-5p, a miRNA that downregulated APP, was paradoxically associated with an increased risk for AD. However, miR-20b-5p also reduced, and the blockade of APP by siRNA likewise reduced calcium influx. As APP plays vital roles in neuronal health and does not exist solely to be the source of "pathogenic" Aβ, the molecular etiology of AD is likely to not just be a disease of "excess" but a disruption of delicate homeostasis.
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    The Longest Common Exemplar Subsequence Problem
    (IEEE, 2018-12) Zhang, Shu; Wang, Ruizhi; Zhu, Daming; Jiang, Haitao; Feng, Haodi; Guo, Jiong; Liu, Xiaowen; BioHealth Informatics, School of Informatics and Computing
    In this paper, we propose to find order conserved subsequences of genomes by finding longest common exemplar subsequences of the genomes. The longest common exemplar subsequence problem is given by two genomes, asks to find a common exemplar subsequence of them, such that the exemplar subsequence length is maximized. We focus on genomes whose genes of the same gene family are in at most s spans. We propose a dynamic programming algorithm with time complexity O(s4 s mn) to find a longest common exemplar subsequence of two genomes with one genome admitting s span genes of the same gene family, where m, n stand for the gene numbers of those two given genomes. Our algorithm can be extended to find longest common exemplar subsequences of more than one genomes.
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    MicroRNA Regulation of Key Proteins Involved in Alzheimer's Disease Pathogenesis
    (2022-06) Wang, Ruizhi; Du, Yansheng; Lahiri, Debomoy K.; Kim, Jungsu; Reeves, Cristian A. Lasagna; Zhou, Feng C.
    Alzheimer’s disease (AD) is a neurodegenerative disease histopathologically characterized by the coexistence of amyloid plaques and neurofibrillary tangles, mainly consisting of amyloid β peptides hyperphosphorylated tau proteins, respectively. Multiple proteins and pathways are involved in the pathogenesis of AD, including Aβ precursor protein (APP), β-site APP-cleaving enzyme (BACE1), neprilysin, endothelin converting enzyme (ECE), repressor element-1 silencing transcription factor (REST), microtubule-associated protein tau, glycogen synthase kinase, and pro-inflammatory cytokines. However, how these proteins and pathways are dysregulated and converge in AD pathogenesis remains unclear. Genetic, epigenetic and environmental factors play important roles in disease progression. MicroRNAs (miRNAs), a group of small noncoding RNAs, are important epigenetic regulators that participate in AD development. We have identified three miRNAs capable of targeting several proteins in different AD-related pathways: miR-181-5p, miR-153-3p and miR-101-3p. We tested miR-181 activity with recombinant reporter gene- MME 3’-UTR constructs. All four miR-181-5p (miR-181a, miR-181b, miR-181c and miR-181d) sequences downregulated the reporter signal. Human differentiated neural cells were transfected with miR-181d-5p mimics. miR-181d-5p treatment significantly reduced MME mRNA levels, protein levels and enzyme activity. In addition, miR-181d-5p increased tau and phosphorylated tau levels proportionally. We further demonstrate that miR-153-3p reduced REST 3’-UTR activities, mRNA and protein levels in multiple human cell lines. Moreover, we show that miR-153-3p, by knocking down REST protein, induces apoptosis in HeLa cells but not differentiated neural cells. In addition, miR-153-3p regulates neuronal differentiation in neuronal stem cells, potentially via REST knockdown. We further found that miR-153 levels were correlated with a reduced likelihood of developing AD. Last, we demonstrated that miR-101-3p reduced ECE1 and GSK3β protein levels in multiple cell lines. miR-101-3p increased REST and pro-inflammatory cytokine secretion in microglia cells. In sum, we tested the hypothesis that miRNAs can serve as the master regulator of AD pathogenesis.
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    MicroRNA-298 reduces levels of human amyloid-β precursor protein (APP), β-site APP-converting enzyme 1 (BACE1) and specific tau protein moieties
    (Springer Nature, 2021) Chopra, Nipun; Wang, Ruizhi; Maloney, Bryan; Nho, Kwangsik; Beck, John S.; Pourshafie, Naemeh; Niculescu, Alexander; Saykin, Andrew J.; Rinaldi, Carlo; Counts, Scott E.; Lahiri, Debomoy K.; Psychiatry, School of Medicine
    Alzheimer's disease (AD) is the most common age-related form of dementia, associated with deposition of intracellular neuronal tangles consisting primarily of hyperphosphorylated microtubule-associated protein tau (p-tau) and extracellular plaques primarily comprising amyloid- β (Aβ) peptide. The p-tau tangle unit is a posttranslational modification of normal tau protein. Aβ is a neurotoxic peptide excised from the amyloid-β precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex. MicroRNAs (miRNAs) are short, single-stranded RNAs that modulate protein expression as part of the RNA-induced silencing complex (RISC). We identified miR-298 as a repressor of APP, BACE1, and the two primary forms of Aβ (Aβ40 and Aβ42) in a primary human cell culture model. Further, we discovered a novel effect of miR-298 on posttranslational levels of two specific tau moieties. Notably, miR-298 significantly reduced levels of ~55 and 50 kDa forms of the tau protein without significant alterations of total tau or other forms. In vivo overexpression of human miR-298 resulted in nonsignificant reduction of APP, BACE1, and tau in mice. Moreover, we identified two miR-298 SNPs associated with higher cerebrospinal fluid (CSF) p-tau and lower CSF Aβ42 levels in a cohort of human AD patients. Finally, levels of miR-298 varied in postmortem human temporal lobe between AD patients and age-matched non-AD controls. Our results suggest that miR-298 may be a suitable target for AD therapy.