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Widespread RNA metabolism impairment in sporadic inclusion body myositis TDP43-proteinopathy

Cortese, A; Plagnol, V; Brady, S; Simone, R; Lashley, T; Acevedo-Arozena, A; de Silva, R; ... Fratta, P; + view all (2014) Widespread RNA metabolism impairment in sporadic inclusion body myositis TDP43-proteinopathy. Neurobiology of Aging , 35 (6) pp. 1491-1498. 10.1016/j.neurobiolaging.2013.12.029. Green open access


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TDP43 protein mislocalization is a hallmark of the neurodegenerative diseases amyotrophic lateral sclerosis and frontotemporal dementia, and mutations in the gene encoding TDP43 cause both disorders, further highlighting its role in disease pathogenesis. TDP43 is a heterogenous ribonucleoprotein, therefore suggesting that alterations in RNA metabolism play a role in these disorders, although direct evidence in patients is lacking. Sporadic inclusion body myositis (sIBM) is the most common acquired myopathy occurring in adults aged older than 50 years and abnormal cytoplasmic accumulations of TDP43 have been consistently described in sIBM myofibers. Here, we exploit high quality RNA from frozen sIBM muscle biopsies for transcriptomic studies on TDP43-proteinopathy patient tissue. Surprisingly, we found widespread sIBM-specific changes in the RNA metabolism pathways themselves. Consistent with this finding, we describe novel RNA binding proteins to mislocalize in the cytoplasm of sIBM myofibers and splicing changes in MAPT, a gene previously shown to play a role in sIBM. Our data indicate widespread alterations of RNA metabolism are a novel aspect of disease pathogenesis in sIBM. These findings also document an association, in TDP43-proteinopathy patients, between heterogenous ribonucleoprotein pathology and RNA metabolism alterations and carry importance for neurodegenerative diseases, such as amyotrophic lateral sclerosis and frontotemporal dementia.

Type: Article
Title: Widespread RNA metabolism impairment in sporadic inclusion body myositis TDP43-proteinopathy
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.neurobiolaging.2013.12.029
Publisher version: http://dx.doi.org/10.1016/j.neurobiolaging.2013.12...
Language: English
Additional information: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Amyotrophic lateral sclerosis, Inclusion body myositis, MAPT, RNA, TDP-43, hnRNP
URI: http://discovery.ucl.ac.uk/id/eprint/1419919
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