title: TAR DNA-Binding protein 43 accumulation in protein aggregate myopathies.
abstract: Protein aggregate myopathies, including myofibrillar myopathies and sporadic inclusion body myositis (sIBM), are characterized by abnormal protein aggregates composed of various muscular and ectopic proteins. Previous studies have shown the crucial role ofdysregulated transcription factors such as neuron-restrictive silencerfactor in the expression of aberrant proteins in myotilinopathies. Here, we assessed possible aberrant expression of TAR DNA-bindingprotein 43 (TDP-43), another factor involved in transcription regulation. TDP-43-immunoreactive intracytoplasmic inclusions were seen in all cases examined of myotilinopathy, desminopathy, and sIBM, and in 1 case of inclusion body myositis with Paget disease of bone and frontotemporal degeneration (IBMPFD). TAR DNA-binding protein 43 colocalized with myotilin and valosin in myotilinopathies and IBMPFD, respectively, but only occasionally colocalized with ubiquitin in myotilinopathies, desminopathies, sIBM, and IBMPFD; this indicates that accumulated TDP-43 is largely not ubiquitinated. Moreover, phosphorylated TDP-43 at Ser403/404 and Ser409/410 accumulated in the cytoplasm of vulnerable fibers but did not always colocalize with nonphosphorylated TDP-43. Cytoplasmic deposition was accompanied by decreased TDP-43 localization in the nuclei of affected fibers. These findings indicate that TDP-43 not only is another protein accumulated in myofibrillar myopathies, sIBM, and IBMPFD but also likely has a role through altered microRNA processing in the abnormal protein production, modification, and accumulation in protein aggregate myopathies.
authors.affiliation: Institut de Neuropatologia, Servei Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, Spain.
authors.forename: Montse
authors.initials: M
authors.lastname: Olivé
authors.forename: Anna
authors.initials: A
authors.lastname: Janué
authors.forename: Dolores
authors.initials: D
authors.lastname: Moreno
authors.forename: Josep
authors.initials: J
authors.lastname: Gámez
authors.forename: Benjamín
authors.initials: B
authors.lastname: Torrejón-Escribano
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
mesh_terms: D000328:Adult; D000368:Aged; D015153:Blotting, Western; D064211:Connectin; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003704:Dementia; D005260:Female; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008840:Microfilament Proteins; D018613:Microscopy, Confocal; D008875:Middle Aged; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D018979:Myositis, Inclusion Body / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000378:metabolism; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D064211:Connectin; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C577290:MYOT protein, human; D008840:Microfilament Proteins; D009124:Muscle Proteins; D010455:Peptides; D025801:Ubiquitin; C046951:valosin