Cited by 111Inflammatory Myopathies and DermatomyositisMuscle Physiology and DisordersUbiquitin and proteasome pathways

Proteasome Inhibition and Aggresome Formation in Sporadic Inclusion-Body Myositis and in Amyloid-β Precursor Protein-Overexpressing Cultured Human Muscle Fibers

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Fratta, Pietro, Engel, W. King, McFerrin, Janis, Davies, Kelvin J.A., Lin, Sharon W., Askanas, Valerie·2005·The American Journal of Pathology

Abstract

The 26S proteasome system is involved in eliminating various proteins, including ubiquitinated misfolded/unfolded proteins, and its inhibition results in cellular accumulation of protein aggregates. Intramuscle-fiber ubiquitinated multiprotein-aggregates are characteristic of sporadic inclusion-body myositis (s-IBM) muscle fibers. Two major types of aggregates exist, containing either amyloid-beta (Abeta) or phosphorylated tau (p-tau). We have now asked whether abnormalities of the 26S proteasome contribute to s-IBM pathogenesis and whether the multiprotein aggregates have features of aggresomes. Using cultured human muscle fibers we also studied the effect of amyloid-beta precursor protein (AbetaPP) overexpression on proteasome function and the influence of proteasome inhibition on aggresome formation. We report that in s-IBM muscle biopsies 26S proteasome subunits were immunodetected in the gamma-tubulin-associated aggresomes, which also contained Abeta, p-tau, ubiquitin, and HSP70. In addition, a) expression of proteasome subunits was greatly increased, b) the 20Salpha proteasome subunit co-immunoprecipitated with AbetaPP/Abeta, and c) the three major proteasomal proteolytic activities were reduced. In cultured muscle fibers, AbetaPP-overexpressing fibers displayed diminished proteasomal proteolytic activities, and addition of proteasome inhibitor strikingly increased aggresome formation. Accordingly, proteasome dysfunction in s-IBM muscle fibers may play a role in accumulation of misfolded, potentially cytotoxic proteins and may be induced by increased intracellular AbetaPP/Abeta.

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  1. Kim KS, Wen GY, Bancher C, Chen J, Sapienza V, Hong H, Wisniewski HM: Detection and quantitation of amyloid B-peptide with 2 monoclonal antibodies. Neurosci Res Commun 1990, 7:113-122

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Authors
Fratta, P., Engel, W. K., McFerrin, J., Davies, K. J. A., Lin, S. W., & Askanas, V.
Affiliations
University of Southern California (US)
Corresponding author
Askanas, Valerie
Venue
The American Journal of Pathology
Publisher
Elsevier BV
Published
2005-08
Volume
167
Issue
2
Pages
517-526
ISSN
0002-9440 (ISSN-L)
OpenAlex
W1987807233
Cited by
111
References
47
Citations by year
2025: 1 · 2024: 5 · 2022: 3 · 2021: 3 · 2020: 4 · 2018: 1 · 2017: 2 · 2016: 3 · 2015: 4 · 2014: 5 · 2013: 7 · 2012: 6
FWCI
9.56
Type
journal article
Language
en
Open access
Locations
  • American Journal Of Pathology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • Muscular Dystrophy Association (AG16768)
  • Myositis Association
  • National Institutes of Health
  • National Institute on Aging (AG 16768, R37AG016768)
Topics
  • Health Sciences › Medicine › Epidemiology › Inflammatory Myopathies and Dermatomyositis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
sporadic inclusion body myositis, proteasome inhibition, aggresomes, 26S proteasome, amyloid precursor protein, amyloid-beta, phosphorylated tau, protein aggregates, misfolded protein accumulation, HSP70, ubiquitin, proteasome dysfunction
MeSH terms
Cells, Cultured, Humans, Amyloid beta-Protein Precursor, tau Proteins, Muscle Fibers, Skeletal, HSP70 Heat-Shock Proteins, Myositis, Inclusion Body, Ubiquitin, Proteasome Endopeptidase Complex, Proteasome Inhibitors

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