title: Nuclear localization of valosin-containing protein in normal muscle and muscle affected by inclusion-body myositis.
abstract: Inclusion-body myopathy with Paget's disease and frontotemporal dementia (IBMPFD) is a disease of muscle, bone, and brain that results from mutations in the gene encoding valosin-containing protein (VCP). The mechanism of disease resulting from VCP mutations is unknown. Previous studies of VCP localization in normal human muscle samples have found a capillary and perinuclear distribution, but not a nuclear localization. Here we demonstrate that VCP is present in both myonuclei and endothelial cell nuclei in normal human muscle tissue. The immunodetection of VCP varies with acetone or paraformaldehyde fixation. Within the nucleus, VCP associates with the nucleolar protein fibrillarin and Werner syndrome protein (Wrnp) in normal and IBMPFD muscle. In patients with inclusion-body myositis (IBM), normal nuclear localization is present and some rimmed vacuoles are lined with VCP. These findings suggest that impairment in the nuclear function of VCP might contribute to the muscle pathology occurring in IBMPFD.
authors.affiliation: Department of Neurology, Division of Neuromuscular Disease, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA. sagreenberg@partners.org
authors.forename: Steven A
authors.initials: SA
authors.lastname: Greenberg
authors.forename: Giles D
authors.initials: GD
authors.lastname: Watts
authors.forename: Virginia E
authors.initials: VE
authors.lastname: Kimonis
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Amato
authors.forename: Jack L
authors.initials: JL
authors.lastname: Pinkus
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000648:ultrastructure; D005090:Exodeoxyribonucleases; D006801:Humans; D016253:Microscopy, Immunoelectron / Q000379:methods; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure*; D018979:Myositis, Inclusion Body / Q000473:pathology*; D053484:RecQ Helicases / Q000378:metabolism; D000074405:Valosin Containing Protein; D000071657:Werner Syndrome Helicase
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; C047458:fibrillarin; D005090:Exodeoxyribonucleases; D000251:Adenosine Triphosphatases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase; C000614178:VCP protein, human; D000074405:Valosin Containing Protein