Nogalska A, Terracciano C, D’Agostino C, et al.. p62/SQSTM1 is overexpressed and prominently accumulated in inclusions of sporadic inclusion-body myositis muscle fibers, and can help differentiating it from polymyositis and dermatomyositis. Acta Neuropathol. 118: 407-413

Department of Neurology, USC Neuromuscular Center, Good Samaritan Hospital, University of Southern California Keck School of Medicine, Los Angeles, CA 90017-1912, USA.
Acta Neuropathologica (Impact Factor: 10.76). 07/2009; 118(3):407-13. DOI: 10.1007/s00401-009-0564-6
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p62, also known as sequestosome1, is a shuttle protein transporting polyubiquitinated proteins for both the proteasomal and lysosomal degradation. p62 is an integral component of inclusions in brains of various neurodegenerative disorders, including Alzheimer disease (AD) neurofibrillary tangles (NFTs) and Lewy bodies in Parkinson disease. In AD brain, the p62 localized in NFTs is associated with phosphorylated tau (p-tau). Sporadic inclusion-body myositis (s-IBM) is the most common progressive muscle disease associated with aging, and its muscle tissue has several phenotypic similarities to AD brain. Abnormal accumulation of intracellular multiprotein inclusions, containing p-tau in the form of paired helical filaments, amyloid-beta, and several other "Alzheimer-characteristic proteins", is a characteristic feature of the s-IBM muscle fiber phenotype. Diminished proteasomal and lysosomal protein degradation appear to play an important role in the formation of intra-muscle-fiber inclusions. We now report that: (1) in s-IBM muscle fibers, p62 protein is increased on both the protein and the mRNA levels, and it is strongly accumulated within, and as a dense peripheral shell surrounding, p-tau containing inclusions, by both the light- and electron-microscopy. Accordingly, our studies provide a new, reliable, and simple molecular marker of p-tau inclusions in s-IBM muscle fibers. The prominent p62 immunohistochemical positivity and pattern diagnostically distinguish s-IBM from polymyositis and dermatomyositis. (2) In normal cultured human muscle fibers, experimental inhibition of either proteasomal or lysosomal protein degradation caused substantial increase of p62, suggesting that similar in vivo mechanisms might contribute to the p62 increase in s-IBM muscle fibers.

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Available from: Chiara Terracciano, Oct 03, 2015
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    • "It acts as a shuttle protein transporting polyubiquitinated proteins for degradation by both the proteasome and the lysosome [26], [27]. It has also been indicated that P62 is a component of many disease-associated intracellular ubiquitinated multiprotein aggregates [28], [29]. On this basis, we used immunofluorescence labeling to examine the expression of p62 in transfected cells and study the role of p62 in aggregate formation in our disease models. "
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    ABSTRACT: Mutations in TPM2 result in a variety of myopathies characterised by variable clinical and morphological features. We used human and mouse cultured cells to study the effects of β-TM mutants. The mutants induced a range of phenotypes in human myoblasts, which generally changed upon differentiation to myotubes. Human myotubes transfected with the E41K-β-TMEGFP mutant showed perinuclear aggregates. The G53ins-β-TMEGFP mutant tended to accumulate in myoblasts but was incorporated into filamentous structures of myotubes. The K49del-β-TMEGFP and E122K-β-TMEGFP mutants induced the formation of rod-like structures in human cells. The N202K-β-TMEGFP mutant failed to integrate into thin filaments and formed accumulations in myotubes. The accumulation of mutant β-TMEGFP in the perinuclear and peripheral areas of the cells was the striking feature in C2C12. We demonstrated that human tissue culture is a suitable system for studying the early stages of altered myofibrilogenesis and morphological changes linked to myopathy-related β-TM mutants. In addition, the histopathological phenotype associated with expression of the various mutant proteins depends on the cell type and varies with the maturation of the muscle cell. Further, the phenotype is a combinatorial effect of the specific amino acid change and the temporal expression of the mutant protein.
    PLoS ONE 09/2013; 8(9):e72396. DOI:10.1371/journal.pone.0072396 · 3.23 Impact Factor
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    • "A different approach to finding a sensitive marker for IBM is to look for markers related to removal of abnormally aggregated proteins. In both animal [17] and human studies [18-20], RV formation has been linked to the impairment of autophagy, a catabolic process that targets cytoplasmic organelles and protein aggregates for lysosomal degradation [21]. Autophagy impairment leads to accumulation of autophagosomes, which can be detected by immunohistochemistry for autophagy proteins LC3 (microtubule-associated protein 1 light chain 3) and p62/SQSTM1; we have recently shown that immunostaining for either LC3 or p62 can replace electron microscopy in the diagnosis of drug-induced autophagic vacuolar myopathies [18,22]. "
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    ABSTRACT: Background Inclusion body myositis (IBM) is a slowly progressive inflammatory myopathy of the elderly that does not show significant clinical improvement in response to steroid therapy. Distinguishing IBM from polymyositis (PM) is clinically important since PM is steroid-responsive; however, the two conditions can show substantial histologic overlap. Results We performed quantitative immunohistochemistry for (1) autophagic markers LC3 and p62 and (2) protein aggregation marker TDP-43 in 53 subjects with pathologically diagnosed PM, IBM, and two intermediate T cell-mediated inflammatory myopathies (polymyositis with COX-negative fibers and possible IBM). The percentage of stained fibers was significantly higher in IBM than PM for all three immunostains, but the markers varied in sensitivity and specificity. In particular, both LC3 and p62 were sensitive markers of IBM, but the tradeoff between sensitivity and specificity was smaller (and diagnostic utility thus greater) for LC3 than for p62. In contrast, TDP-43 immunopositivity was highly specific for IBM, but the sensitivity of this test was low, with definitive staining present in just 67% of IBM cases. Conclusions To differentiate IBM from PM, we thus recommend using a panel of LC3 and TDP-43 antibodies: the finding of <14% LC3-positive fibers helps exclude IBM, while >7% of TDP-43-positive fibers strongly supports a diagnosis of IBM. These data provide support for the hypothesis that disruption of autophagy and protein aggregation contribute to IBM pathogenesis.
    07/2013; 1(1). DOI:10.1186/2051-5960-1-29
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    • "Earlier work has shown that LCOs bind to a plethora of protein aggregates including hepatic protein inclusion bodies termed Mallory–Denk.9, 27 To investigate whether LCOs could be utilized for general detection of protein inclusion bodies, we used muscle biopsies from s-IBM patients, as protein inclusion bodies in s-IBM muscle fibers have been reported to be composed of a variety of aggregated proteins.18–24 Biopsies from two to five s-IBM patients with p62-positive inclusion bodies were stained with the following LCOs: tetramer formyl thiophene acetic acid (q-FTAA), pentamer hydrogen thiophene acetic acid (p-HTAA), pentamer formyl thiophene acetic acid (p-FTAA), or heptamer formyl thiophene acetic acid (h-FTAA; Figure 1 A). "
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    ABSTRACT: Small hydrophobic ligands identifying intracellular protein deposits are of great interest, as protein inclusion bodies are the pathological hallmark of several degenerative diseases. Here we report that fluorescent amyloid ligands, termed luminescent conjugated oligothiophenes (LCOs), rapidly and with high sensitivity detect protein inclusion bodies in skeletal muscle tissue from patients with sporadic inclusion body myositis (s-IBM). LCOs having a conjugated backbone of at least five thiophene units emitted strong fluorescence upon binding, and showed co-localization with proteins reported to accumulate in s-IBM protein inclusion bodies. Compared with conventional amyloid ligands, LCOs identified a larger fraction of immunopositive inclusion bodies. When the conjugated thiophene backbone was extended with terminal carboxyl groups, the LCO revealed striking spectral differences between distinct protein inclusion bodies. We conclude that 1) LCOs are sensitive, rapid and powerful tools for identifying protein inclusion bodies and 2) LCOs identify a wider range of protein inclusion bodies than conventional amyloid ligands.
    ChemBioChem 03/2013; 14(5). DOI:10.1002/cbic.201200731 · 3.09 Impact Factor
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