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.
Myotilinopathies and desminopathies are subgroups of myofibrillar myopathies (MFM) caused by mutations in myotilin and desmin genes, respectively. They are characterized by the presence of protein aggregates in muscle cells. As oxidation of proteins facilitates their aggregation and makes them more resistant to proteolysis, the present study was geared to analyze oxidative stress in MFM. For this purpose, markers of glycoxidation, lipoxidation and nitration were examined with gel electrophoresis and Western blotting, single immunohistochemistry, and double- and triple-labeling immunofluorescence and confocal microscopy in muscle biopsies from patients suffering from myotilinopathy and desminopathy. Increased levels of glycation-end products (AGEs), N-carboxymethyl-lysine (CML) and N-carboxyethyl-lysine (CEL), malondialdehyde-lysine (MDAL), 4-hydroxynonenal (HNE) and nitrotyrosine (N-tyr) were found in MFM. Furthermore, aberrant expression of AGE, CML, CEL, MDAL and HNE, as well as of neuronal, inducible and endothelial nitric oxide synthases (nNOS, iNOS, eNOS), and superoxide dismutase 2 (SOD2), was found in muscle fibers containing protein aggregates in myotilinopathies and desminopathies. AGE, ubiquitin and p62 co-localized in several muscle fibers in MFM. As oxidized proteins are vulnerable to misfolding and are resistant to degradation by the UPS, the present observations support a link between oxidative stress, protein aggregation and abnormal protein deposition in MFMs.
(2008) Neuropathology and Applied Neurobiology 34, 76-87 Expression of mutant ubiquitin (UBB +1 ) and p62 in myotilinopathies and desminopathies Protein aggregates in muscle cells are the morphological hallmark of myofibrillar myopathies, including myotilinopathies and desminopathies. The aim of the present study is to analyse the expression of mutant ubiquitin (UBB +1 ), an aberrant form of ubiquitin which accumulates in certain disorders characterized by intracellular aggregates of proteins, and p62, a multimeric signal protein which plays an active role in aggregate formation, in muscle biopsies from patients suffering from myotilinopathy and desminopathy in order to gain understanding of the mechanisms leading to protein aggregation in these disorders. Single immunohistochemistry, and singleand double-labelling immunofluorescence and confocal microscopy for UBB +1 and p62, has been performed in muscle biopsies from patients suffering from myotilinopathy and desminopathy. Strong UBB +1 immunoreactivity, colocalizing with myotilin aggregates, was found in muscle fibres in myotilinopathies. UBB +1 accumulation, colocalizing with desmin aggregates, also occurs in desminopathies. In addition, strong p62 immunoreactivity colocalizing with myotilin aggregates was observed in myotilinopathies. Similarly, p62 immunoreactivity colocalizing with desmin aggregates was found in desminopathies. The present findings suggest that accumulation of protein aggregates in myotilinopathies and in desminopathies may be related with UBB +1 /abnormal protein complexes which are resistant to proteasome degradation. Furthermore, these observations suggest a relationship between the presence of p62 and the formation of inclusions in different subtypes of myofibrillar myopathies.
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