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Mutant ubiquitin UBB⁺¹ is accumulated in sporadic inclusion-body myositis muscle fibers

From the USC Neuromuscular Center (Drs. Fratta, Engel, Vattemi, and Askanas), Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA; and Netherlands Institute for Brain Research (Drs. Van Leeuwen and Hol), Research Group Molecular Misreading, Amsterdam, The Netherlands.

Address correspondence and reprint requests to Dr. Valerie Askanas, USC Neuromuscular Center, Good Samaritan Hospital, 637 South Lucas Avenue, Los Angeles, CA 90017-1912; e-mail: askanas{at}hsc.usc.edu

Mutant ubiquitin (UBB⁺¹), a product of "molecular misreading," is toxic to cells because its ubiquitinated form inhibits the proteasome, contributing to accumulation of misfolded proteins and their ensuing toxicity. The authors demonstrate in 10 sporadic inclusion body myositis (s-IBM) muscle biopsies that UBB⁺¹ is accumulated in aggregates containing amyloid-ß and phosphorylated-tau. In s-IBM, UBB⁺¹ may be pathogenic by inhibiting proteasome, thereby promoting accumulation of cytotoxic misfolded amyloid-ß and phosphorylated-tau.

Received February 18, 2004. Accepted in final form May 14, 2004.

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