title: Activation of the γ-secretase complex and presence of γ-secretase-activating protein may contribute to Aβ42 production in sporadic inclusion-body myositis muscle fibers.
abstract: The muscle-fiber phenotype of sporadic inclusion-body myositis (s-IBM), the most common muscle disease associated with aging, shares several pathological abnormalities with Alzheimer disease (AD) brain, including accumulation of amyloid-β 42 (Aβ42) and its cytotoxic oligomers. The exact mechanisms leading to Aβ42 production within s-IBM muscle fibers are not known. Aβ42 and Aβ40 are generated after the amyloid-precursor protein (AβPP) is cleaved by β-secretase and the γ-secretase complex. Aβ42 is considered more cytotoxic than Aβ40, and it has a higher propensity to oligomerize, form amyloid fibrils, and aggregate. Recently, we have demonstrated in cultured human muscle fibers that experimental inhibition of lysosomal enzyme activities leads to Aβ42 oligomerization. In s-IBM muscle, we here demonstrate prominent abnormalities of the γ-secretase complex, as evidenced by: a) increase of γ-secretase components, namely active presenilin 1, presenilin enhancer 2, nicastrin, and presence of its mature, glycosylated form; b) increase of mRNAs of these γ-secretase components; c) increase of γ-secretase activity; d) presence of an active form of a newly-discovered γ-secretase activating protein (GSAP); and e) increase of GSAP mRNA. Furthermore, we demonstrate that experimental inhibition of lysosomal autophagic enzymes in cultured human muscle fibers a) activates γ-secretase, and b) leads to posttranslational modifications of AβPP and increase of Aβ42. Since autophagy is impaired in biopsied s-IBM muscle, the same mechanism might be responsible for its having increased γ-secretase activity and Aβ42 production. Accordingly, improving lysosomal function might be a therapeutic strategy for s-IBM patients.
authors: USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA 90017‐1912, USA.
authors: Anna
authors: A
authors: Nogalska
authors: Carla
authors: C
authors: D'Agostino
authors: W King
authors: WK
authors: Engel
authors: Valerie
authors: V
authors: Askanas
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D018979:Myositis, Inclusion Body / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism*; D017285:Polymyositis / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; C552289:GSAP protein, human; D010446:Peptide Fragments; D011506:Proteins; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases