NOGO is increased and binds to BACE1 in sporadic inclusion-body myositis and in A beta PP-overexpressing cultured human muscle fibers.
Increased amyloid-beta precursor protein (A beta PP) and amyloid-beta (A beta) accumulation appear to be upstream steps in the pathogenesis of sporadic inclusion-body myositis (s-IBM). BACE1, participating in A beta production is also increased in s-IBM muscle fibers. Nogo-B and Nogo-A belong to a family of integral membrane reticulons, and Nogo-B binding to BACE1 blocks BACE1 access to A beta PP, decreasing A beta production. We studied Nogo-B and Nogo-A in s-IBM muscle and in our IBM muscle culture models, based on A beta PP-overexpression or ER-stress-induction in cultured human muscle fibers (CHMFs). We report that: (1) in biopsied s-IBM fibers, Nogo-B is increased, accumulates in aggregates, is immuno-co-localized with BACE1, and binds to BACE1; Nogo-A is undetectable. (2) In CHMFs, (a) A beta PP overexpression increases Nogo-B, Nogo-A, and BACE1, (b) ER stress increases BACE1 but decreases Nogo-B and Nogo-A, (c) Nogo-B and Nogo-A associate with BACE1. Accordingly, two novel mechanisms, A beta PP overexpression and ER stress, are involved in Nogo-B and Nogo-A expression in human muscle. We propose that in s-IBM muscle the Nogo-B increase may represent an attempt by muscle fiber to decrease A beta production. However, the increase of Nogo-B seems insufficient because A beta continues to accumulate and the disease progresses. We propose that manipulations, which increase Nogo-B in s-IBM muscle might offer a new therapeutic opportunity.
Wojcik
Slawomir
S
USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, 637 S. Lucas Ave, Los Angeles, CA 90017-1912, USA.
Engel
W King
WK
Yan
Riqiang
R
McFerrin
Janis
J
Askanas
Valerie
V
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000503:physiopathology; D009185:Myelin Proteins / Q000378:metabolism*; D018979:Myositis, Inclusion Body / Q000378:metabolism* / Q000503:physiopathology; D000070798:Nogo Proteins; D018384:Oxidative Stress / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D009185:Myelin Proteins; D000070798:Nogo Proteins; C000603199:RTN4 protein, human; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human