Widespread RNA metabolism impairment in sporadic inclusion body myositis TDP43-proteinopathy.
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.
MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, London, UK; Department of General Neurology, C. Mondino National Institute of Neurology Foundation, IRCCS, Italy.
Andrea
A
Cortese
UCL Genetics Institute, University College London, London, UK.
Vincent
V
Plagnol
MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, London, UK.
Stefen
S
Brady
The Reta Lila Weston Institute, UCL Institute of Neurology, London, UK.
Roberto
R
Simone
Department of Molecular Neuroscience, Queen Square Brain Bank, UCL Institute of Neurology, London, UK.
Tammaryn
T
Lashley
Mammalian Genetics Unit, MRC, Oxfordshire, UK.
Abraham
A
Acevedo-Arozena
The Reta Lila Weston Institute, UCL Institute of Neurology, London, UK.
Rohan
R
de Silva
MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, London, UK; Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, UK.
Linda
L
Greensmith
MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, London, UK; Department of Molecular Neuroscience, Queen Square Brain Bank, UCL Institute of Neurology, London, UK.
Janice
J
Holton
MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, London, UK.
Michael G
MG
Hanna
MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, London, UK; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
Elizabeth M C
EM
Fisher
MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, London, UK; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK. Electronic address: pietro.fratta@gmail.com.
Pietro
P
Fratta
D000368:Aged; D000690:Amyotrophic Lateral Sclerosis; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D057180:Frontotemporal Dementia / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D018979:Myositis, Inclusion Body / Q000235:genetics*; D011485:Protein Binding; D021381:Protein Transport; D012313:RNA / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D057177:TDP-43 Proteinopathies / Q000235:genetics*
D004268:DNA-Binding Proteins; D016601:RNA-Binding Proteins; D012313:RNA
Amyotrophic lateral sclerosis; Inclusion body myositis; MAPT; RNA; TDP-43; hnRNP