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

Daniel Pirici, Rik Vandenberghe, Rosa V 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 journalArticle

47 Citations (Scopus)

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 2006
Externally publishedYes

Fingerprint

Frontotemporal Lobar Degeneration
Synucleins
Neurons
Intranuclear Inclusion Bodies
Inclusion Bodies
Nuclear Envelope
Oligodendroglia
Microglia
Astrocytes
Atrophy
Proteins
Pathology
Staining and Labeling
Antibodies
Brain

Keywords

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

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neuroscience(all)

Cite this

Characterization of ubiquitinated intraneuronal inclusions in a novel Belgian frontotemporal lobar degeneration family. / Pirici, Daniel; Vandenberghe, Rik; Rademakers, Rosa V; Dermaut, Bart; Cruts, Marc; Vennekens, Krist'l; Cuijt, Ivy; Lübke, Ursula; Ceuterick, Chantal; Martin, Jean Jacques; Van Broeckhoven, Christine; Kumar-Singh, Samir.

In: Journal of Neuropathology and Experimental Neurology, Vol. 65, No. 3, 03.2006, p. 289-301.

Research output: Contribution to journalArticle

Pirici, D, Vandenberghe, R, Rademakers, RV, Dermaut, B, Cruts, M, Vennekens, K, Cuijt, I, Lübke, U, Ceuterick, C, Martin, JJ, Van Broeckhoven, C & Kumar-Singh, S 2006, 'Characterization of ubiquitinated intraneuronal inclusions in a novel Belgian frontotemporal lobar degeneration family', Journal of Neuropathology and Experimental Neurology, vol. 65, no. 3, pp. 289-301. https://doi.org/10.1097/01.jnen.0000205147.39210.c7
Pirici, Daniel ; Vandenberghe, Rik ; Rademakers, Rosa V ; Dermaut, Bart ; Cruts, Marc ; Vennekens, Krist'l ; Cuijt, Ivy ; Lübke, Ursula ; Ceuterick, Chantal ; Martin, Jean Jacques ; Van Broeckhoven, Christine ; Kumar-Singh, Samir. / Characterization of ubiquitinated intraneuronal inclusions in a novel Belgian frontotemporal lobar degeneration family. In: Journal of Neuropathology and Experimental Neurology. 2006 ; Vol. 65, No. 3. pp. 289-301.
@article{d4f0f7d65d714ff395d766fc2f4a6015,
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.",
keywords = "Frontotemporal dementia, Frontotemporal lobar degeneration, Intranuclear inclusions, Ubiquitin-positive inclusions",
author = "Daniel Pirici and Rik Vandenberghe and Rademakers, {Rosa V} and Bart Dermaut and Marc Cruts and Krist'l Vennekens and Ivy Cuijt and Ursula L{\"u}bke and Chantal Ceuterick and Martin, {Jean Jacques} and {Van Broeckhoven}, Christine and Samir Kumar-Singh",
year = "2006",
month = "3",
doi = "10.1097/01.jnen.0000205147.39210.c7",
language = "English (US)",
volume = "65",
pages = "289--301",
journal = "American Journal of Psychotherapy",
issn = "0002-9564",
publisher = "Lippincott Williams and Wilkins",
number = "3",

}

TY - JOUR

T1 - Characterization of ubiquitinated intraneuronal inclusions in a novel Belgian frontotemporal lobar degeneration family

AU - Pirici, Daniel

AU - Vandenberghe, Rik

AU - Rademakers, Rosa V

AU - Dermaut, Bart

AU - Cruts, Marc

AU - Vennekens, Krist'l

AU - Cuijt, Ivy

AU - Lübke, Ursula

AU - Ceuterick, Chantal

AU - Martin, Jean Jacques

AU - Van Broeckhoven, Christine

AU - Kumar-Singh, Samir

PY - 2006/3

Y1 - 2006/3

N2 - 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.

AB - 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.

KW - Frontotemporal dementia

KW - Frontotemporal lobar degeneration

KW - Intranuclear inclusions

KW - Ubiquitin-positive inclusions

UR - http://www.scopus.com/inward/record.url?scp=33646771829&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33646771829&partnerID=8YFLogxK

U2 - 10.1097/01.jnen.0000205147.39210.c7

DO - 10.1097/01.jnen.0000205147.39210.c7

M3 - Article

C2 - 16651890

AN - SCOPUS:33646771829

VL - 65

SP - 289

EP - 301

JO - American Journal of Psychotherapy

JF - American Journal of Psychotherapy

SN - 0002-9564

IS - 3

ER -