title: Proteasome inhibition and aggresome formation in sporadic inclusion-body myositis and in amyloid-beta precursor protein-overexpressing cultured human muscle fibers.
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.
authors.affiliation: Department of Neurology, USC Neuromuscular Center, Good Samaritan Hospital, Los Angeles, CA 90017-1912, USA.
authors.forename: Pietro
authors.initials: P
authors.lastname: Fratta
authors.forename: W King
authors.initials: WK
authors.lastname: Engel
authors.forename: Janis
authors.initials: J
authors.lastname: McFerrin
authors.forename: Kelvin J A
authors.initials: KJ
authors.lastname: Davies
authors.forename: Sharon W
authors.initials: SW
authors.lastname: Lin
authors.forename: Valerie
authors.initials: V
authors.lastname: Askanas
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D002478:Cells, Cultured; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D018979:Myositis, Inclusion Body / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D025801:Ubiquitin / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D018840:HSP70 Heat-Shock Proteins; D061988:Proteasome Inhibitors; D025801:Ubiquitin; D016875:tau Proteins; D046988:Proteasome Endopeptidase Complex