title: Characterization of ubiquitinated intraneuronal inclusions in a novel Belgian frontotemporal lobar degeneration family.
abstract: The most common histologic feature in patients with frontotemporal lobar degeneration (FTLD) is intracellular brain inclusions of yet uncharacterized proteins that react with antiubiquitin (Ub) antibodies, but not with tau or synuclein (FTLD-U). We identified a four-generation Belgian FTLD family in which 8 patients had dominantly inherited FTLD. In one patient, we showed frontotemporal atrophy with filamentous Ub-positive intracellular inclusions in absence of tau pathology or any alterations in the levels of soluble tau. We characterized the cellular and subcellular localization and morphology of the inclusions. Ub-positive inclusions predominantly occurred within neurons (>97%), but were also observed within oligodendroglia (approximately 2%) and microglia (<1%), but not within astroglia. Regarding the subcellular localization, the intranuclear inclusions (INI) were up to approximately four-fold more frequent than the cytoplasmic inclusions, although the latter were more specific to neurons. The INIs frequently appeared spindle-shaped and 3-dimensional confocal reconstructions identified flattened, leaf-like structures. Ultrastructurally, straight 10- to 18-nm-diameter filaments constituted the spindle-shaped inclusions that occurred in close proximity to the nuclear membrane. Staining for HSP40, p62, and valosin/p97 was observed in only a minority of the inclusions. Whereas the precise nature of the protein remains elusive, characterization of such familial FTLD-U patients would be helpful in identifying a common denominator in the pathogenesis of familial and the more prevalent sporadic FTLD-U.
authors.affiliation: Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB8), Institute Born-Bunge, University of Antwerp, Belgium.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pirici
authors.forename: Rik
authors.initials: R
authors.lastname: Vandenberghe
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.forename: Bart
authors.initials: B
authors.lastname: Dermaut
authors.forename: Marc
authors.initials: M
authors.lastname: Cruts
authors.forename: Krist'l
authors.initials: K
authors.lastname: Vennekens
authors.forename: Ivy
authors.initials: I
authors.lastname: Cuijt
authors.forename: Ursula
authors.initials: U
authors.lastname: Lübke
authors.forename: Chantal
authors.initials: C
authors.lastname: Ceuterick
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Martin
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
authors.forename: Samir
authors.initials: S
authors.lastname: Kumar-Singh
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001530:Belgium; D048430:Cell Shape; D004252:DNA Mutational Analysis; D003704:Dementia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D025801:Ubiquitin; D051844:alpha-Synuclein; D016875:tau Proteins