Increased BACE1 mRNA and noncoding BACE1-antisense transcript in sporadic inclusion-body myositis muscle fibers--possibly caused by endoplasmic reticulum stress.
Sporadic inclusion-body myositis (s-IBM) is the most common muscle disease of older persons. Its muscle-fiber phenotype shares several molecular similarities with Alzheimer-disease (AD) brain, including increased AbetaPP, accumulation of amyloid-beta (Abeta), and increased BACE1 protein. Abeta42 is prominently increased in AD brain and within s-IBM fibers, and its oligomers are putatively toxic to both tissues--accordingly, minimizing Abeta42 production can be a therapeutic objective in both tissues. The pathogenic development of s-IBM is unknown, including the mechanisms of BACE1 protein increase. BACE1 is an enzyme essential for production from AbetaPP of Abeta42 and Abeta40, which are proposed to be detrimental within s-IBM muscle fibers. Novel noncoding BACE1-antisense (BACE1-AS) was recently shown (a) to be increased in AD brain, and (b) to increase BACE1 mRNA and BACE1 protein. We studied BACE1-AS and BACE1 transcripts by real-time PCR (a) in 10 s-IBM and 10 age-matched normal muscle biopsies; and (b) in our established ER-Stress-Human-Muscle-Culture-IBM Model, in which we previously demonstrated increased BACE1 protein. Our study demonstrated for the first time that (a) in s-IBM biopsies BACE1-AS and BACE1 transcripts were significantly increased, suggesting that their increased expression can be responsible for the increase of BACE1 protein; and (b) experimental induction of ER stress significantly increased both BACE1-AS and BACE1 transcripts, suggesting that ER stress can participate in their induction in s-IBM muscle. Accordingly, decreasing BACE1 through a targeted downregulation of its regulatory BACE1-AS, or reducing ER stress, might be therapeutic strategies in s-IBM, assuming that it would not impair any normal cellular functions of BACE1.
Nogalska
Anna
A
USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA, USA.
Engel
W King
WK
USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA, USA.
Askanas
Valerie
V
USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA, USA. Electronic address: askanas@usc.edu.
D000368:Aged; D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis*; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis*; D016373:DNA, Antisense / Q000096:biosynthesis*; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018979:Myositis, Inclusion Body / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013312:Stress, Physiological / Q000502:physiology
D016373:DNA, Antisense; D012333:RNA, Messenger; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human