Characterization of ubiquitinated intraneuronal inclusions in a novel Belgian frontotemporal lobar degeneration family

Daniel Pirici, Rik Vandenberghe, Rosa Rademakers, Bart Dermaut, Marc Cruts, Krist'l Vennekens, Ivy Cuijt, Ursula Lübke, Chantal Ceuterick, Jean Jacques Martin, Christine Van Broeckhoven, Samir Kumar-Singh

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)289-301
Number of pages13
JournalJournal of Neuropathology and Experimental Neurology
Volume65
Issue number3
DOIs
StatePublished - Mar 1 2006

Keywords

  • Frontotemporal dementia
  • Frontotemporal lobar degeneration
  • Intranuclear inclusions
  • Ubiquitin-positive inclusions

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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