Molecular pathology and pathogenesis of inclusion-body myositis.
We summarize the molecular phenotype, diagnostic criteria, and the newest advances related to seeking the pathogenic mechanism(s) of sporadic inclusion-body myositis (s-IBM), a muscle disease usually of persons over age 50. On the basis of our research, several processes seem to be important in relation to the still-speculative pathogenesis: 1) increased transcription and accumulation of amyloid-beta precursor protein (AbetaPP), and accumulation of its proteolytic fragment Abeta; 2) abnormal accumulation of cholesterol, caveolin-1, and apolipoprotein E; 3) oxidative stress; 4) accumulations of intramuscle fiber multiprotein aggregates; and 5) evidence that unfolded/misfolded proteins participate in s-IBM pathogenesis. Our basic hypothesis is that overexpression of AbetaPP within the aging muscle fibers is an early upstream event causing a subsequent pathogenic cascade.
Askanas
Valerie
V
USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, California 90017-1912, USA. askanas@usc.edu
Engel
W King
WK
D000375:Aging / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D001057:Apolipoproteins E / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D006801:Humans; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000648:ultrastructure; D009154:Mutation; D018979:Myositis, Inclusion Body / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D017510:Protein Folding
D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D051242:Caveolin 1; D002784:Cholesterol