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Abnormalities of NBR1, a novel autophagy-associated protein, in muscle fibers of sporadic inclusion-body myositis

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Abstract

Intra-muscle fiber accumulation of ubiquitinated protein aggregates containing several conformationally modified proteins, including amyloid-β and phosphorylated tau, is characteristic of the pathologic phenotype of sporadic inclusion-body myositis (s-IBM), the most common progressive degenerative myopathy of older persons. Abnormalities of protein-degradation, involving both the 26S proteasome and autophagic-lysosomal pathways, were previously demonstrated in s-IBM muscle. NBR1 is a ubiquitin-binding scaffold protein importantly participating in autophagic degradation of ubiquitinated proteins. Whereas abnormalities of p62, a ubiquitin-binding protein, were previously described in s-IBM, abnormalities of NBR1 have not been reported in s-IBM. We have now identified in s-IBM muscle biopsies that NBR1, by: (a) immunohistochemistry, was strongly accumulated within s-IBM muscle-fiber aggregates, where it closely co-localized with p62, ubiquitin, and phosphorylated tau; (b) immunoblots, was increased threefold (p < 0.001); and (c) immunoprecipitation, was associated with p62 and LC3. By real-time PCR, NBR1 mRNA was increased twofold (p < 0.01). None of the various disease- and normal-control muscle biopsies had any NBR1 abnormality. In cultured human muscle fibers, NBR1 also physically associated with both p62 and LC3, and experimental inhibition of either the 26S proteasome or the lysosomal activity resulted in NBR1 increase. Our demonstration of NBR1 abnormalities in s-IBM provides further evidence that altered protein degradation pathways may be critically involved in the s-IBM pathogenesis. Accordingly, attempts to unblock defective protein degradation might be a therapeutic strategy for s-IBM patients.

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Acknowledgments

Maggie Baburyan provided technical assistance in electronmicroscopy. We are grateful to Dr Michael Jakowec of the USC Department of Neurology for allowing us to use his real-time PCR equipment. This work was supported by a grant from the Muscular Dystrophy Association to VA, and the Helen Lewis Research Fund.

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Authors and Affiliations

  1. Department of Neurology, USC Neuromuscular Center, University of Southern California Keck School of Medicine, Good Samaritan Hospital, 637 S. Lucas Ave, Los Angeles, CA, 90017-1912, USA

    Carla D’Agostino, Anna Nogalska, Mafalda Cacciottolo, W. King Engel & Valerie Askanas

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  1. Carla D’Agostino
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  2. Anna Nogalska
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  3. Mafalda Cacciottolo
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  4. W. King Engel
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  5. Valerie Askanas
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Corresponding author

Correspondence to Valerie Askanas.

Additional information

Dr Nogalska is on leave from the Department of Biochemistry, Medical University of Gdansk, Gdansk, Poland. Mafalda Cacciottolo is a Ruth Ziegler Neuromuscular Fellow.

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D’Agostino, C., Nogalska, A., Cacciottolo, M. et al. Abnormalities of NBR1, a novel autophagy-associated protein, in muscle fibers of sporadic inclusion-body myositis. Acta Neuropathol 122, 627–636 (2011). https://doi.org/10.1007/s00401-011-0874-3

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  • DOI: https://doi.org/10.1007/s00401-011-0874-3

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