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(American Journal of Pathology. 2005;167:517-526.)
© 2005 American Society for Investigative Pathology

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

Pietro Fratta*, W. King Engel*, Janis McFerrin*, Kelvin J.A. Davies{dagger}, Sharon W. Lin{dagger} and Valerie Askanas*

From the Department of Neurology,* University of Southern California Neuromuscular Center, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles; and the Ethel Mercy Andrus Gerontology Center and Division of Molecular and Computational Biology,{dagger} University of Southern California, Los Angeles, California

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 char-acteristic of sporadic inclusion-body myositis (s-IBM) muscle fibers. Two major types of aggregates exist, containing either amyloid-ß (Aß) 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-ß precursor protein (AßPP) 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 Aß, p-tau, ubiquitin, and HSP70. In addition, a) expression of proteasome subunits was greatly increased, b) the 20S{alpha} proteasome subunit co-immunoprecipitated with AßPP/Aß, and c) the three major proteasomal proteolytic activities were reduced. In cultured muscle fibers, AßPP-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 AßPP/Aß.




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