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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

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: 9.78). 07/2009; 118(3):407-13. DOI: 10.1007/s00401-009-0564-6
Source: PubMed

ABSTRACT 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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    • "Eleven patients had received a treatment with either low-dose steroids alone (n = 5) or combined with azathrioprine or methotrexate (n = 6) before biopsy. The definitive diagnosis of s-IBM was based on established clinico-pathological criteria [5] [22] and sarcoplasmic immunoreactivity for b-amyloid, phosphorylated tau, p62 [23] or TDP-43 protein [24] within >1% of muscle fibers. For comparison with other inflammatory myopathies, muscle biopsies from patients referred to the Reference Center for Neuromuscular Diseases, Institut de Myologie, Hô pital Pitié-Salpetrière who displayed treatment-responsive Table 1 Demographic data of patients. "
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    • "p62 and TDP-43 immunoreactive fibers were observed in all presumed d s-IBM cases and in 37 and 31% of p s-IBM, respectively. That means that: 1) a posteriori all d s-IBM patients were well classified and finally, by the presence of PHF evidenced by p62 (Nogalska et al., 2009) fulfill all the Griggs criteria for d s-IBM. The percentage was increased to 42% by adding the cases of p s-IBM re-classified with each marker. "
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    • "The features of protein aggregation, abnormal mitochondria and distension of endo/sarcoplasmic reticulum that are typical of many acquired and genetic muscle diseases suggest an impairment, more than an exacerbation, of autophagic flux. For instance, protein aggregates that are positive for ubiquitin and p62/SQSTM1 proteins have been recently described in muscle of patients affected by sporadic Inclusion Body Myositis as well as in different tissuespecific autophagy knockout mice [25] [26] [27]. To clarify the role of basal autophagy we have generated two conditional knockout mice for the critical Atg7 gene to block autophagy specifically in skeletal muscle [28]. "
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