title: Pathological heterogeneity of frontotemporal lobar degeneration with ubiquitin-positive inclusions delineated by ubiquitin immunohistochemistry and novel monoclonal antibodies.
abstract: Frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) is a common neuropathological subtype of frontotemporal dementia. Although this subtype of frontotemporal dementia is defined by the presence of ubiquitin-positive but tau- and alpha-synuclein-negative inclusions, it is unclear whether all cases of FTLD-U have the same underlying pathogenesis. Examination of tissue sections from FTLD-U brains stained with anti-ubiquitin antibodies revealed heterogeneity in the morphological characteristics of pathological inclusions among subsets of cases. Three types of FTLD-U were delineated based on morphology and distribution of ubiquitin-positive inclusions. To address the hypothesis that FTLD-U is pathologically heterogeneous, novel monoclonal antibodies (mAbs) were generated by immunization of mice with high molecular mass (Mr > 250 kd) insoluble material prepared by biochemical fractionation of FTLD-U brains. Novel mAbs were identified that immunolabeled all of the ubiquitin-positive inclusions in one subset of FTLD-U cases, whereas other mAbs stained the ubiquitin-positive inclusions in a second subset of cases. These novel mAbs did not stain inclusions in other neurodegenerative disorders, including tauopathies and alpha-synucleinopathies. Therefore, ubiquitin immunohistochemistry and the immunostaining properties of the novel mAbs generated here suggest that FTLD-U is pathologically heterogeneous. Identification of the disease proteins recognized by these mAbs will further advance understanding of molecular substrates of FTLD-U neurodegenerative pathways.
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 3600 Spruce St., 3rd Floor Maloney Bldg., Philadelphia, PA 19104, USA.
authors.forename: Deepak M
authors.initials: DM
authors.lastname: Sampathu
authors.forename: Manuela
authors.initials: M
authors.lastname: Neumann
authors.forename: Linda K
authors.initials: LK
authors.lastname: Kwong
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Chou
authors.forename: Matthew
authors.initials: M
authors.lastname: Micsenyi
authors.forename: Adam
authors.initials: A
authors.lastname: Truax
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bruce
authors.forename: Murray
authors.initials: M
authors.lastname: Grossman
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
mesh_terms: D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000276:immunology*; D003704:Dementia / Q000473:pathology*; D005260:Female; D005625:Frontal Lobe / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000737:chemistry*; D008297:Male; D051379:Mice; D008875:Middle Aged; D013702:Temporal Lobe / Q000473:pathology*; D025801:Ubiquitin / Q000032:analysis* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D025801:Ubiquitin