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Trends Pharmacol Sci ; 40(8): 565-576, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31326236


Computational drug repurposing has the ability to remarkably reduce drug development time and cost in an era where these factors are prohibitively high. Several examples of successful repurposed drugs exist in fields such as oncology, diabetes, leprosy, inflammatory bowel disease, among others, however computational drug repurposing in neurodegenerative disease has presented several unique challenges stemming from the lack of validation methods and difficulty in studying heterogenous diseases of aging. Here, we examine existing approaches to computational drug repurposing, including molecular, clinical, and biophysical methods, and propose data sources and methods to advance computational drug repurposing in neurodegenerative disease using Alzheimer's disease as an example.

J Exp Med ; 211(10): 1937-45, 2014 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-25155018


Frontotemporal dementia (FTD) is the most common cause of dementia in people under 60 yr of age and is pathologically associated with mislocalization of TAR DNA/RNA binding protein 43 (TDP-43) in approximately half of cases (FLTD-TDP). Mutations in the gene encoding progranulin (GRN), which lead to reduced progranulin levels, are a significant cause of familial FTLD-TDP. Grn-KO mice were developed as an FTLD model, but lack cortical TDP-43 mislocalization and neurodegeneration. Here, we report retinal thinning as an early disease phenotype in humans with GRN mutations that precedes dementia onset and an age-dependent retinal neurodegenerative phenotype in Grn-KO mice. Retinal neuron loss in Grn-KO mice is preceded by nuclear depletion of TDP-43 and accompanied by reduced expression of the small GTPase Ran, which is a master regulator of nuclear import required for nuclear localization of TDP-43. In addition, TDP-43 regulates Ran expression, likely via binding to its 3'-UTR. Augmented expression of Ran in progranulin-deficient neurons restores nuclear TDP-43 levels and improves their survival. Our findings establish retinal neurodegeneration as a new phenotype in progranulin-deficient FTLD, and suggest a pathological loop involving reciprocal loss of Ran and nuclear TDP-43 as an underlying mechanism.

Proteínas de Ligação a DNA/metabolismo , Demência Frontotemporal/complicações , Regulação da Expressão Gênica/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Doenças Neurodegenerativas/fisiopatologia , Retina/fisiopatologia , Transporte Ativo do Núcleo Celular/fisiologia , Fatores Etários , Animais , Eletrorretinografia , Demência Frontotemporal/genética , Granulinas , Humanos , Modelos Lineares , Camundongos , Camundongos Knockout , Mutação/genética , Doenças Neurodegenerativas/etiologia , Tomografia de Coerência Óptica , Proteína ran de Ligação ao GTP/metabolismo
J Biophotonics ; 7(9): 724-34, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24019106


Retinal tissue is damaged during inflammation in Multiple Sclerosis. We assessed molecular changes in inflamed murine retinal cultures by Raman spectroscopy. Partial Least Squares-Discriminant analysis (PLS-DA) was able to classify retina cultures as inflamed with high accuracy. Using Multivariate Curve Resolution (MCR) analysis, we deconvolved 6 molecular components suffering dynamic changes along inflammatory process. Those include the increase of immune mediators (Lipoxygenase, iNOS and TNFα), changes in molecules involved in energy production (Cytochrome C, phenylalanine and NADH/NAD+) and decrease of Phosphatidylcholine. Raman spectroscopy combined with multivariate analysis allows monitoring the evolution of retina inflammation.

Imagem Molecular , Doenças Retinianas/patologia , Análise Espectral Raman , Animais , Células Cultivadas , Análise Discriminante , Metabolismo Energético , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Análise dos Mínimos Quadrados , Metabolismo dos Lipídeos , Camundongos , Análise Multivariada , Doenças Retinianas/imunologia , Doenças Retinianas/metabolismo , Células Ganglionares da Retina/patologia , Fatores de Tempo