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.

Cytoplasmic TDP‐43 accumulation in cells of the adrenal medulla in individuals with or without amyotrophic lateral sclerosis

“…Similar discrepancies were reported in myopathies, 18 that is, not all TDP-43-positive deposits were stained with anti-pTDP-43 antibodies, and not all pTDP-43-positive inclusions were recognized by anti-TDP-43 antibodies in protein-aggregate myopathies.…”

“…However, general organs outside the CNS have rarely been studied regarding the accumulation of TDP-43. In general human organs, TDP-43 accumulates frequently in the cytoplasm of the muscles of patients with sporadic inclusion body myositis and oculopharyngeal muscular dystrophy, and in other protein-aggregate myopathies; 18 however, TDP-43 accumulation has not been reported in other general human organs. Recently, the TDP-43 profile was investigated using Western blot analysis in lysates of circulating lymphocytes, which showed that TDP-43 was expressed at approximately the same levels in whole lymphocyte lysates of ALS patients, their relatives, and controls.…”

“…15 Although TDP-43 is expressed ubiquitously in the nuclei of all cells, the accumulation of TDP-43 outside the CNS has not been reported, with the exception of the muscles of patients with protein-aggregate myopathies. 18 During our preliminary study, we observed a marked accumulation of TDP-43 and pTDP-43 in the cytoplasm of renal tubular cells, and less frequently in the cells of several organs; however, the majority of these immunoreactivities were nonspecific biotin reactions. Conversely, many TDP-43-positive and pTDP-43-negative cytoplasmic accumulations were observed in the adrenal medulla.…”

“…In protein-aggregate myopathies, which might be caused by alterations in autophagic degradation pathways, TDP-43 accumulation is found in rimmed vacuoles that show autophagosomal characteristics. 18 These findings suggest that autophagosomes are one of the intracellular compartments in which TDP-43 degradation occurs, and that the disruption of autophagic pathways leads to TDP-43 accumulation in autophagosomes and related compartments. Recent studies have shown that, under stress, TDP-43 is recruited to stress granules in a variety of cells.…”

Myofibrillar myopathies

“…1H), synemin, Xin, TAR DNA-binding protein 43 (TDP-43), and co-chaperones including αB-crystallin (Fig. 1E), heat shock protein (Hsp) 27 ( Fig.1I) and DNAJB2 [8][9][10][11][12][13][14][15][16]. Additional abnormal accumulation of several other proteins was documented in myotilinopathy and desminopathy.…”