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.
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.
Nogalska
Anna
A
Department of Neurology, USC Neuromuscular Center, Good Samaritan Hospital, University of Southern California Keck School of Medicine, Los Angeles, CA 90017-1912, USA.
Terracciano
Chiara
C
D'Agostino
Carla
C
King Engel
W
W
Askanas
Valerie
V
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D015153:Blotting, Western; D002478:Cells, Cultured; D003882:Dermatomyositis / Q000175:diagnosis; D003937:Diagnosis, Differential; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008247:Lysosomes / Q000378:metabolism; D008856:Microscopy, Fluorescence; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000166:cytology; D018979:Myositis, Inclusion Body / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017285:Polymyositis / Q000175:diagnosis; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071456:Sequestosome-1 Protein; D016875:tau Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D016875:tau Proteins; D046988:Proteasome Endopeptidase Complex