In AbetaPP-overexpressing cultured human muscle fibers proteasome inhibition enhances phosphorylation of AbetaPP751 and GSK3beta activation: effects mitigated by lithium and apparently relevant to sporadic inclusion-body myositis.
Muscle fiber degeneration in sporadic inclusion-body myositis (s-IBM) is characterized by accumulation of multiprotein aggregates, including aggregated amyloid-beta (Abeta)-precursor protein 751 (AbetaPP751), Abeta, phosphorylated tau, and other 'Alzheimer-characteristic' proteins. Proteasome inhibition is an important component of the s-IBM pathogenesis. In brains of Alzheimer's disease (AD) patients and AD transgenic-mouse models, phosphorylation of neuronal AbetaPP695 (p-AbetaPP) on Thr668 (equivalent to T724 of AbetaPP751) is considered detrimental because it increases generation of cytotoxic Abeta and induces tau phosphorylation. Activated glycogen synthase kinase3beta (GSK3beta) is involved in phosphorylation of both AbetaPP and tau. Lithium, an inhibitor of GSK3beta, was reported to reduce levels of both the total AbetaPP and p-AbetaPP in AD animal models. In relation to s-IBM, we now show for the first time that (1) In AbetaPP-overexpressing cultured human muscle fibers (human muscle culture IBM model: (a) proteasome inhibition significantly increases GSK3beta activity and AbetaPP phosphorylation, (b) treatment with lithium decreases (i) phosphorylated-AbetaPP, (ii) total amount of AbetaPP, (iii) Abeta oligomers, and (iv) GSK3beta activity; and (c) lithium improves proteasome function. (2) In biopsied s-IBM muscle fibers, GSK3beta is significantly activated and AbetaPP is phosphorylated on Thr724. Accordingly, treatment with lithium, or other GSK3beta inhibitors, might benefit s-IBM patients.
Terracciano
Chiara
C
Department of Neurology, USC Neuromuscular Center, University of Southern California Keck, School of Medicine, Good Samaritan Hospital, Los Angeles, California 90017, USA.
Nogalska
Anna
A
Engel
W King
WK
Askanas
Valerie
V
D000368:Aged; D000369:Aged, 80 and over; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D004721:Endoplasmic Reticulum / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D018021:Lithium Chloride / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism; D018979:Myositis, Inclusion Body / Q000473:pathology*; D018384:Oxidative Stress / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism*; D061988:Proteasome Inhibitors; D020033:Protein Isoforms / Q000378:metabolism; D013912:Threonine / Q000378:metabolism; D046509:Tissue Culture Techniques
D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D061988:Proteasome Inhibitors; D020033:Protein Isoforms; D013912:Threonine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex; D018021:Lithium Chloride