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

Andrea Cortese, Vincent Plagnol, Stefen Brady, Roberto Simone, Tammaryn Lashley, Abraham Acevedo-Arozena, Rohan De Silva, Linda Greensmith, Janice Holton, Michael G. Hanna, Elizabeth M C Fisher, Pietro Fratta

Research output: Contribution to journalArticlepeer-review


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 50years 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.

Original languageEnglish
Pages (from-to)1491-1498
Number of pages8
JournalNeurobiology of Aging
Issue number6
Publication statusPublished - Jun 2014


  • Amyotrophic lateral sclerosis
  • HnRNP
  • Inclusion body myositis
  • MAPT
  • RNA
  • TDP-43

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Ageing
  • Developmental Biology
  • Geriatrics and Gerontology
  • Medicine(all)


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