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      RNA polymerase III drives alternative splicing of the potassium channel–interacting protein contributing to brain complexity and neurodegeneration

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          Abstract

          An RNA polymerase III–transcribed noncoding RNA promotes alternative splicing of KCNIP4, altering amyloid precursor protein processing and contributing to neurodegeneration.

          Abstract

          Alternative splicing generates protein isoforms that are conditionally or differentially expressed in specific tissues. The discovery of factors that control alternative splicing might clarify the molecular basis of biological and pathological processes. We found that IL1-α−dependent up-regulation of 38A, a small ribonucleic acid (RNA) polymerase III–transcribed RNA, drives the synthesis of an alternatively spliced form of the potassium channel–interacting protein (KCNIP4). The alternative KCNIP4 isoform cannot interact with the γ-secretase complex, resulting in modification of γ-secretase activity, amyloid precursor protein processing, and increased secretion of β-amyloid enriched in the more toxic Aβ x-42 species. Notably, synthesis of the variant KCNIP4 isoform is also detrimental to brain physiology, as it results in the concomitant blockade of the fast kinetics of potassium channels. This alternative splicing shift is observed at high frequency in tissue samples from Alzheimer’s disease patients, suggesting that RNA polymerase III cogenes may be upstream determinants of alternative splicing that significantly contribute to homeostasis and pathogenesis in the brain.

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          Most cited references31

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          Inflammation in Alzheimer disease: driving force, bystander or beneficial response?

          Alzheimer disease is a progressive dementia with unknown etiology that affects a growing number of the aging population. Increased expression of inflammatory mediators in postmortem brains of people with Alzheimer disease has been reported, and epidemiological studies link the use of anti-inflammatory drugs with reduced risk for the disorder. On the initial basis of this kind of evidence, inflammation has been proposed as a possible cause or driving force of Alzheimer disease. If true, this could have important implications for the development of new treatments. Alternatively, inflammation could simply be a byproduct of the disease process and may not substantially alter its course. Or components of the inflammatory response might even be beneficial and slow the disease. To address these possibilities, we need to determine whether inflammation in Alzheimer disease is an early event, whether it is genetically linked with the disease and whether manipulation of inflammatory pathways changes the course of the pathology. Although there is still little evidence that inflammation triggers or promotes Alzheimer disease, increasing evidence from mouse models suggests that certain inflammatory mediators are potent drivers of the disease. Related factors, on the other hand, elicit beneficial responses and can reduce disease.
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            Morphology and growth, tumorigenicity, and cytogenetics of human neuroblastoma cells in continuous culture.

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              Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms.

              Mutations in human presenilin (PS) genes cause aggressive forms of familial Alzheimer's disease. Presenilins are polytopic proteins that harbour the catalytic site of the gamma-secretase complex and cleave many type I transmembrane proteins including beta-amyloid precursor protein (APP), Notch and syndecan 3. Contradictory results have been published concerning whether PS mutations cause 'abnormal' gain or (partial) loss of function of gamma-secretase. To avoid the possibility that wild-type PS confounds the interpretation of the results, we used presenilin-deficient cells to analyse the effects of different clinical mutations on APP, Notch, syndecan 3 and N-cadherin substrate processing, and on gamma-secretase complex formation. A loss in APP and Notch substrate processing at epsilon and S3 cleavage sites was observed with all presenilin mutants, whereas APP processing at the gamma site was affected in variable ways. PS1-Delta9 and PS1-L166P mutations caused a reduction in beta-amyloid peptide Abeta40 production whereas PS1-G384A mutant significantly increased Abeta42. Interestingly PS2, a close homologue of PS1, appeared to be a less efficient producer of Abeta than PS1. Finally, subtle differences in gamma-secretase complex assembly were observed. Overall, our results indicate that the different mutations in PS affect gamma-secretase structure or function in multiple ways.
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                Author and article information

                Journal
                J Cell Biol
                J. Cell Biol
                jcb
                The Journal of Cell Biology
                The Rockefeller University Press
                0021-9525
                1540-8140
                30 May 2011
                : 193
                : 5
                : 851-866
                Affiliations
                [1 ]Department of Oncology, Biology, and Genetics, National Institute for Cancer Research , [2 ]Department of Physics , and [3 ]Department of Experimental Medicine, University of Genoa, 16132 Genoa, Italy
                [4 ]Department of Biochemistry and Molecular Biology, University of Parma, 43121 Parma, Italy
                [5 ]Department of Health Sciences, University of Molise, Campobasso, 86100 Molise, Italy
                Author notes
                Correspondence to Aldo Pagano: aldo.pagano@ 123456unige.it

                S. Massone, I. Vassallo, and M. Castelnuovo contributed equally to this paper.

                Article
                201011053
                10.1083/jcb.201011053
                3105541
                21624954
                9a0b9d6e-4882-4481-a204-2ee03485cd7a
                © 2011 Massone et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

                History
                : 9 November 2010
                : 2 May 2011
                Categories
                Research Articles
                Article

                Cell biology
                Cell biology

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