Abstract
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.
Highlights
TDP43 is a major component of the inclusions that characterize frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) central nervous system pathology, and sporadic inclusion body myositis muscle pathology (D’Agostino et al, 2011; Hernandez Lain et al, 2011; Küsters et al, 2009; Mackenzie et al, 2010; Olivé et al, 2009; Salajegheh et al, 2009; Weihl et al, 2008)
We investigated upregulation and changes in the autoregulation pattern by microarray and targeted Nanostring analysis and found no evidence of differences in sporadic inclusion body myositis (sIBM) samples, one sample, that had by far the most severe TDP43 pathology, had an increase in TARDBP messenger RNA (mRNA) and changes in the autoregulation pattern compatible with an attempt to compensate for high levels of TDP43 protein (Fig. 1). sIBM4 was characterized by having the longest interval between onset and biopsy (Supplementary Table 1)
In conclusion our data reveal widespread changes in RNA metabolism pathways occurring in sIBM TDP43-proteinopathy and are supported by the finding that other novel heterogenous ribonucleoprotein (hnRNP) mislocalize and accumulate in the cytoplasm of sIBM TDP43-proteinopathy (Kim et al, 2013)
Summary
The numerous recent findings of cytoplasmic TDP43 inclusions in sIBM muscle fibers (D’Agostino et al, 2011; Hernandez Lain et al, 2011; Olivé et al, 2009; Salajegheh et al, 2009; Weihl et al, 2008), have strengthened the link between sIBM and neurodegenerative disorders, supported by: (1) age of disease onset and its unresponsiveness to immunosuppressive treatment; (2) identification of numerous neurodegeneration-characteristic proteins in the ubiquitinated inclusions of sIBM muscle, such as abeta and tau (Supplementary Table 2) (Askanas et al, 2009; Mirabella et al, 1996); and (3) identification of mutations in the VCP gene as a cause of both ALS, and a complex phenotype which comprises an hereditary form of inclusion body myopathy associated with FTD (Johnson et al, 2010; Nalbandian et al, 2011). We find widespread disruption in RNA metabolism and for the first time, we believe, document such changes in patient TDP43proteinopathy tissue
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