title: Valosin containing protein associated inclusion body myopathy: abnormal vacuolization, autophagy and cell fusion in myoblasts.
abstract: Inclusion body myopathy associated with Paget's disease and frontotemporal dementia (IBMPFD) is caused by mutations in the valosin containing protein (VCP) gene. The disease is associated with progressive proximal muscle weakness, inclusions and vacuoles in muscle fibers, malfunction in the bone remodeling process resulting in Paget's disease, and premature frontotemporal dementia. VCP is involved in several cellular processes related to the endoplasmic reticulum associated degradation of proteins. To understand the pathological mechanisms underlying the myopathy in IBMPFD, we have studied the cellular consequences of VCP mutations in human primary myoblasts. Our results revealed that patients' myoblasts accumulate large vacuoles. Lysosomal membrane proteins Lamp1 and Lamp2 show increased molecular weights in patients' myoblasts due to differential N-glycosylation. Additionally, mutant myoblasts show increased autophagy when cultured in the absence of nutrients, as well as defective cell fusion and increased apoptosis. Our results elucidate that VCP mutations result in disturbances in several cellular processes, which will help us in the understanding of the pathological mechanisms resulting in muscle weakness and other features of VCP associated disease.
authors.affiliation: Department of Pediatrics, Division of Genetics and Metabolism, University of California, Irvine, CA 92868, USA.
authors.forename: Jouni
authors.initials: J
authors.lastname: Vesa
authors.forename: Hailing
authors.initials: H
authors.lastname: Su
authors.forename: Giles D
authors.initials: GD
authors.lastname: Watts
authors.forename: Sabine
authors.initials: S
authors.lastname: Krause
authors.forename: Maggie C
authors.initials: MC
authors.lastname: Walter
authors.forename: Barbara
authors.initials: B
authors.lastname: Martin
authors.forename: Charles
authors.initials: C
authors.lastname: Smith
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Wallace
authors.forename: Virginia E
authors.initials: VE
authors.lastname: Kimonis
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism*; D000328:Adult; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001343:Autophagy / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D002459:Cell Fusion / Q000379:methods; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000502:physiology; D005260:Female; D057180:Frontotemporal Dementia / Q000150:complications; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins / Q000235:genetics; D008297:Male; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D009154:Mutation / Q000235:genetics; D032446:Myoblasts / Q000473:pathology / Q000502:physiology* / Q000648:ultrastructure; D018979:Myositis, Inclusion Body / Q000378:metabolism* / Q000473:pathology; D010001:Osteitis Deformans / Q000150:complications; D000074405:Valosin Containing Protein; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D000251:Adenosine Triphosphatases; D053148:Caspase 3; D018797:Cell Cycle Proteins; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins; D000074405:Valosin Containing Protein; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; C497811:LAMP2 protein, human; C000614178:VCP protein, human