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 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 language | English |
|---|---|
| Pages (from-to) | 1491-1498 |
| Number of pages | 8 |
| Journal | Neurobiology of Aging |
| Volume | 35 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Jun 2014 |
Fingerprint
Keywords
- 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)
Cite this
Widespread RNA metabolism impairment in sporadic inclusion body myositis TDP43-proteinopathy. / Cortese, Andrea; Plagnol, Vincent; Brady, Stefen; Simone, Roberto; Lashley, Tammaryn; Acevedo-Arozena, Abraham; De Silva, Rohan; Greensmith, Linda; Holton, Janice; Hanna, Michael G.; Fisher, Elizabeth M C; Fratta, Pietro.
In: Neurobiology of Aging, Vol. 35, No. 6, 06.2014, p. 1491-1498.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Widespread RNA metabolism impairment in sporadic inclusion body myositis TDP43-proteinopathy
AU - Cortese, Andrea
AU - Plagnol, Vincent
AU - Brady, Stefen
AU - Simone, Roberto
AU - Lashley, Tammaryn
AU - Acevedo-Arozena, Abraham
AU - De Silva, Rohan
AU - Greensmith, Linda
AU - Holton, Janice
AU - Hanna, Michael G.
AU - Fisher, Elizabeth M C
AU - Fratta, Pietro
PY - 2014/6
Y1 - 2014/6
N2 - 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.
AB - 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.
KW - Amyotrophic lateral sclerosis
KW - HnRNP
KW - Inclusion body myositis
KW - MAPT
KW - RNA
KW - TDP-43
UR - http://www.scopus.com/inward/record.url?scp=84903372127&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84903372127&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2013.12.029
DO - 10.1016/j.neurobiolaging.2013.12.029
M3 - Article
VL - 35
SP - 1491
EP - 1498
JO - Neurobiology of Aging
JF - Neurobiology of Aging
SN - 0197-4580
IS - 6
ER -