title: Proteasomal expression, induction of immunoproteasome subunits, and local MHC class I presentation in myofibrillar myopathy and inclusion body myositis.
abstract: Inclusion body myositis (IBM) and myofibrillar myopathy (MM) are diseases characterized by the abnormal accumulation of proteins in muscle fibers, including desmin, alphaB-crystallin, gelsolin, actin, kinases, and phospho-tau, along with ubiquitin in muscle fibers, suggesting abnormal protein degradation as a possible cause of the surplus myopathy. Since the ubiquitin-proteasome system plays a crucial role in non-lysosomal protein degradation, the present study has examined by immunohistochemistry the expression of components of the catalytic core of 20S proteasomes and its regulators: 19S and PA28alpha/beta, and the expression of immunoproteasome subunits LMP2, LMP7, and MECL1 in 8 patients with MM and 10 patients with IBM. The patients with MM were from 6 unrelated families, 2 sporadic cases, I with autosomal recessive and 5 with autosomal dominant inheritance. One sporadic patient had a de novo R406W mutation in the desmin gene, and 1 patient with autosomal dominant MM had a single amino acid deletion at position 366 in the desmin gene. Increased immunoreactivity to 20S, 19S, and PA28alpha/beta colocalizing abnormal protein deposits, as revealed in consecutive serial sections, was seen in all cases with MM and IBM. In all cases, the subunits of the immunoproteasome LMP2, LMP7, and MECL1 colocalized with proteasomal immunoreactivity and abnormal protein accumulation. Immunohistochemistry revealed focal MHC class I immunoreactivity in the cytoplasmic membrane of muscle fibers in IBM and in association with protein aggregates in IBM, and to a lesser degree, in MM. The present findings provide a link between abnormal protein accumulation and altered proteasomal expression in IBM and MM.
authors.affiliation: Instituto de Neuropatología, Servicio de Anatomía Patológica, Hospital Universitario de Bellvitge, Hospitalet de Llobregat, Spain. 8082ifa@comb.es
authors.forename: Isidro
authors.initials: I
authors.lastname: Ferrer
authors.forename: Begoña
authors.initials: B
authors.lastname: Martín
authors.forename: José G
authors.initials: JG
authors.lastname: Castaño
authors.forename: José J
authors.initials: JJ
authors.lastname: Lucas
authors.forename: Dolores
authors.initials: D
authors.lastname: Moreno
authors.forename: Montse
authors.initials: M
authors.lastname: Olivé
mesh_terms: D000251:Adenosine Triphosphatases / Q000276:immunology / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017951:Antigen Presentation / Q000276:immunology; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000276:immunology* / Q000378:metabolism; D004252:DNA Mutational Analysis; D003893:Desmin / Q000172:deficiency / Q000235:genetics; D010450:Endopeptidases / Q000276:immunology / Q000378:metabolism; D005260:Female; D005820:Genetic Testing; D015395:Histocompatibility Antigens Class I / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000276:immunology* / Q000378:metabolism; D009124:Muscle Proteins / Q000276:immunology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D009154:Mutation / Q000235:genetics; D009210:Myofibrils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020914:Myopathies, Structural, Congenital / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D018979:Myositis, Inclusion Body / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex; D021122:Protein Subunits / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics; D011506:Proteins / Q000276:immunology / Q000378:metabolism
chemical_list: D003893:Desmin; D015395:Histocompatibility Antigens Class I; D009097:Multienzyme Complexes; D009124:Muscle Proteins; C085047:PSME1 protein, human; D021122:Protein Subunits; D011506:Proteins; C071313:LMP-2 protein; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; C098948:PSMB10 protein, human; D046988:Proteasome Endopeptidase Complex; C119011:26S proteasome non-ATPase regulatory subunit 13; D000251:Adenosine Triphosphatases