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      Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease

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          Most cited references 274

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          Network medicine: a network-based approach to human disease.

          Given the functional interdependencies between the molecular components in a human cell, a disease is rarely a consequence of an abnormality in a single gene, but reflects the perturbations of the complex intracellular and intercellular network that links tissue and organ systems. The emerging tools of network medicine offer a platform to explore systematically not only the molecular complexity of a particular disease, leading to the identification of disease modules and pathways, but also the molecular relationships among apparently distinct (patho)phenotypes. Advances in this direction are essential for identifying new disease genes, for uncovering the biological significance of disease-associated mutations identified by genome-wide association studies and full-genome sequencing, and for identifying drug targets and biomarkers for complex diseases.
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            Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease.

            Some cases of Alzheimer's disease are inherited as an autosomal dominant trait. Genetic linkage studies have mapped a locus (AD3) associated with susceptibility to a very aggressive form of Alzheimer's disease to chromosome 14q24.3. We have defined a minimal cosegregating region containing the AD3 gene, and isolated at least 19 different transcripts encoded within this region. One of these transcripts (S182) corresponds to a novel gene whose product is predicted to contain multiple transmembrane domains and resembles an integral membrane protein. Five different missense mutations have been found that cosegregate with early-onset familial Alzheimer's disease. Because these changes occurred in conserved domains of this gene, and are not present in normal controls, they are likely to be causative of AD3.
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              A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells.

              Mammalian cells proteolytically release (shed) the extracellular domains of many cell-surface proteins. Modification of the cell surface in this way can alter the cell's responsiveness to its environment and release potent soluble regulatory factors. The release of soluble tumour-necrosis factor-alpha (TNF-alpha) from its membrane-bound precursor is one of the most intensively studied shedding events because this inflammatory cytokine is so physiologically important. The inhibition of TNF-alpha release (and many other shedding phenomena) by hydroxamic acid-based inhibitors indicates that one or more metalloproteinases is involved. We have now purified and cloned a metalloproteinase that specifically cleaves precursor TNF-alpha. Inactivation of the gene in mouse cells caused a marked decrease in soluble TNF-alpha production. This enzyme (called the TNF-alpha-converting enzyme, or TACE) is a new member of the family of mammalian adamalysins (or ADAMs), for which no physiological catalytic function has previously been identified. Our results should facilitate the development of therapeutically useful inhibitors of TNF-alpha release, and they indicate that an important function of adamalysins may be to shed cell-surface proteins.
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                Author and article information

                Journal
                Medicinal Research Reviews
                Med Res Rev
                Wiley
                01986325
                September 2019
                September 2019
                January 09 2019
                : 39
                : 5
                : 1730-1778
                Affiliations
                [1 ]Faculty of Medical Technology; Center of Data Mining and Biomedical Informatics, Mahidol University; Bangkok Thailand
                [2 ]Faculty of Medical Technology; Center for Research and Innovation, Mahidol University; Bangkok Thailand
                [3 ]Institute of Molecular Biosciences; Mahidol University; Nakhon Pathom Thailand
                [4 ]Centre National de la Recherche Scientifique; Paris France
                10.1002/med.21563
                © 2019

                http://doi.wiley.com/10.1002/tdm_license_1.1

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