Browsing by Author "Maloney, Bryan"
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Item 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 MedicineItem Are pulmonary fibrosis and Alzheimer's disease linked? Shared dysregulation of two miRNA species and downstream pathways accompany both disorders(American Society for Biochemistry and Molecular Biology, 2017-12-08) Lahiri, Debomoy K.; Maloney, Bryan; Greig, Nigel H.; Psychiatry, School of MedicineItem A cardinal sin when researching neuropsin/KLK8: Thou shalt validate antibodies(Elsevier, 2017-09) Lahiri, Debomoy K.; Konar, Arpita; Thakur, Mahendra K.; Maloney, Bryan; Psychiatry, School of MedicineItem CORRECTION: Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer’s disease(Springer Nature, 2020-03-02) Ray, Balmiki; Maloney, Bryan; Sambamurti, Kumar; Karnati, Hanuma K.; Nelson, Peter T.; Greig, Nigel H.; Lahiri, Debomoy K.; Psychiatry, School of MedicineCorrection to: Translational Psychiatry 10.1038/s41398-020-0709-x published online 03 February 2020 The original article contained few errors: Hanuma K. Karnati’s name was misstated in the author list, references 2 and 55 referred to the wrong sources, and the authors wanted to expand on their discussion of ChEIs on page 13. These errors have all been updated in the XML, PDF, and HTML versions of this article.Item Crossing the “Birth Border” for Epigenetic Effects(Elsevier, 2022) Lahiri, Debomoy K.; Maloney, Bryan; Song, Weihong; Sokol, Deborah K.; Psychiatry, School of MedicineItem Early-life events may trigger biochemical pathways for Alzheimer's disease: the "LEARn" model(Springer-Verlag, 2008-12) Lahiri, Debomoy K.; Zawia, Nasser H.; Greig, Nigel H.; Sambamurti, Kumar; Maloney, Bryan; Department of Psychiatry, IU School of MedicineAlzheimer's disease (AD), the most common form of dementia among the elderly, manifests mostly late in adult life. However, it is presently unclear when the disease process starts and how long the pathobiochemical processes take to develop. Our goal is to address the timing and nature of triggers that lead to AD. To explain the etiology of AD, we have recently proposed a "Latent Early-life Associated Regulation" (LEARn) model, which postulates a latent expression of specific genes triggered at the developmental stage. This model integrates both the neuropathological features (e.g., amyloid-loaded plaques and tau-laden tangles) and environmental factors (e.g., diet, metal exposure, and hormones) associated with the disease. Environmental agents perturb gene regulation in a long-term fashion, beginning at early developmental stages, but these perturbations do not have pathological results until significantly later in life. The LEARn model operates through the regulatory region (promoter) of the gene and by affecting the methylation status within the promoter of specific genes.Item FMRP Regulates the Nuclear Export of Adam9 and Psen1 mRNAs: Secondary Analysis of an N 6 -Methyladenosine Dataset(Nature Publishing group, 2020-07-01) Westmark, Cara J.; Maloney, Bryan; Alisch, Reid S.; Sokol, Deborah K.; Lahiri, Debomoy K.; Psychiatry, School of MedicineFragile X mental retardation protein (FMRP) binds to and regulates the translation of amyloid-β protein precursor (App) mRNA, but the detailed mechanism remains to be determined. Differential methylation of App mRNA could underlie FMRP binding, message localization and translation efficiency. We sought to determine the role of FMRP and N6-methyladeonsine (m6A) on nuclear export of App mRNA. We utilized the m6A dataset by Hsu and colleagues to identify m6A sites in App mRNA and to determine if the abundance of message in the cytoplasm relative to the nucleus is altered in Fmr1 knockout mouse brain cortex. Given that processing of APP to Aβ and soluble APP alpha (sAPPα) contributes to disease phenotypes, we also investigated whether Fmr1KO associates with nuclear export of the mRNAs for APP protein processing enzymes, including β-site amyloid cleaving enzyme (Bace1), A disintegrin and metalloproteinases (Adams), and presenilins (Psen). Fmr1KO did not alter the nuclear/cytoplasmic abundance of App mRNA. Of 36 validated FMRP targets, 35 messages contained m6A peaks but only Agap2 mRNA was selectively enriched in Fmr1KO nucleus. The abundance of the APP processing enzymes Adam9 and Psen1 mRNA, which code for a minor alpha-secretase and gamma-secretase, respectively, were selectively enriched in wild type cytoplasm.Item Functional Characterization of Three Single-Nucleotide Polymorphisms Present in the Human APOε Promoter Sequence: Differential Effects in Neuronal Cells and on DNA–Protein Interactions(Wiley, 2010-01-05) Maloney, Bryan; Ge, Yuan-Wen; Petersen, Ronald C.; Hardy, John; Rogers, Rogers; Pérez-Tur, Jordi; Lahiri, Debomoy K.; Psychiatry, School of MedicineVariations in levels of apolipoprotein E (ApoE) have been tied to the risk and progression of Alzheimer’s disease (AD). Our group has previously compared and contrasted the promoters of the mouse and human ApoE gene (APOE) promoter sequences and found notable similarities and significant differences that suggest the importance of the APOE promoter’s role in the human disease. We examine here three specific single-nucleotide polymorphisms within the human APOE promoter region, specifically at −491 (A/T), −427 (T/C), and at −219 (G/T) upstream from the +1 transcription start site. The −219 and −491 polymorphic variations have significant association with instance of AD, and −491AA has significant risk even when stratified for the APOEε4 allele. We also show significant effects on reporter gene expression in neuronal cell cultures, and, notably, these effects are modified by species origin of the cells. The −491 and −219 polymorphisms may have an interactive effect in addition to any independent activity. DNA–protein interactions differ between each polymorphic state. We propose SP1 and GATA as candidates for regulatory control of the −491 and −219 polymorphic sites. This work’s significance lies in drawing connection among APOE promoter polymorphisms’ associations with AD to functional promoter activity differences and specific changes in DNA–protein interactions in cell culture-based assays. Taken together, these results suggest that APOE expression levels are a risk factor for AD irrespective of APOEε4 allele status.Item Gene × environment interaction by a longitudinal epigenome-wide association study (LEWAS) overcomes limitations of genome-wide association study (GWAS)(Future Medicine Ltd., 2012-12) Lahiri, Debomoy K.; Maloney, Bryan; Department of Psychiatry, School of MedicineThe goal of genome-wide association studies is to identify SNPs unique to disease. It usually involves a single sampling from subjects' lifetimes. While primary DNA sequence variation influences gene-expression levels, expression is also influenced by epigenetics, including the ‘somatic epitype’ (GSE), an epigenotype acquired postnatally. While genes are inherited, and novel polymorphisms do not routinely appear, GSE is fluid. Furthermore, GSE could respond to environmental factors (such as heavy metals) and to differences in exercise, maternal care and dietary supplements – all of which postnatally modify oxidation or methylation of DNA, leading to altered gene expression. Change in epigenetic status may be critical for the development of many diseases. We propose a ‘longitudinal epigenome-wide association study’, wherein GSE are measured at multiple time points along with subjects' histories. This Longitudinal epigenome-wide association study, based on the ‘dynamic’ somatic epitype over the ‘static’ genotype, merits further investigation.Item 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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