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

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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 would be helpful in identifying a common denominator in the pathogenesis of familial and the more prevalent sporadic FTLD-U.
Keywords
frontotemporal lobar degeneration, frontotemporal dementia, intranuclear inclusions, ubiquitin-positive inclusions, VALOSIN-CONTAINING PROTEIN, MOTOR-NEURON DISEASE, PICKS-DISEASE, PAGET-DISEASE, ALZHEIMERS-DISEASE, BINDING PROTEIN, BODY MYOPATHY, DEMENTIA, TAU, MUTATIONS

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Chicago
Pirici, Daniel, Rik Vandenberghe, Rosa Rademakers, Bart Dermaut, Marc Cruts, Krist’l Vennekens, Ivy Cuijt, et al. 2006. “Characterization of Ubiquitinated Intraneuronal Inclusions in a Novel Belgian Frontotemporal Lobar Degeneration Family.” Journal of Neuropathology and Experimental Neurology 65 (3): 289–301.
APA
Pirici, D., Vandenberghe, R., Rademakers, R., Dermaut, B., Cruts, M., Vennekens, K., Cuijt, I., et al. (2006). Characterization of ubiquitinated intraneuronal inclusions in a novel Belgian frontotemporal lobar degeneration family. JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY, 65(3), 289–301.
Vancouver
1.
Pirici D, Vandenberghe R, Rademakers R, Dermaut B, Cruts M, Vennekens K, et al. Characterization of ubiquitinated intraneuronal inclusions in a novel Belgian frontotemporal lobar degeneration family. JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY. 2006;65(3):289–301.
MLA
Pirici, Daniel, Rik Vandenberghe, Rosa Rademakers, et al. “Characterization of Ubiquitinated Intraneuronal Inclusions in a Novel Belgian Frontotemporal Lobar Degeneration Family.” JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY 65.3 (2006): 289–301. Print.
@article{3200530,
  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 ({\textrangle} 97\%), but were also observed within oligodendroglia (approximately 2\%) and microglia ({\textlangle} 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 would be helpful in identifying a common denominator in the pathogenesis of familial and the more prevalent sporadic FTLD-U.},
  author       = {Pirici, Daniel and Vandenberghe, Rik and Rademakers, Rosa and Dermaut, Bart and Cruts, Marc and Vennekens, Krist'l and Cuijt, Ivy and Lubke, Ursula and Ceuterick, Chantal and Martin, Jean-Jacques and Van Broeckhoven, Christine and Kumar-Singh, Samir},
  issn         = {0022-3069},
  journal      = {JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY},
  keyword      = {frontotemporal lobar degeneration,frontotemporal dementia,intranuclear inclusions,ubiquitin-positive inclusions,VALOSIN-CONTAINING PROTEIN,MOTOR-NEURON DISEASE,PICKS-DISEASE,PAGET-DISEASE,ALZHEIMERS-DISEASE,BINDING PROTEIN,BODY MYOPATHY,DEMENTIA,TAU,MUTATIONS},
  language     = {eng},
  number       = {3},
  pages        = {289--301},
  title        = {Characterization of ubiquitinated intraneuronal inclusions in a novel Belgian frontotemporal lobar degeneration family},
  url          = {http://dx.doi.org/10.1097/01.jnen.0000205147.39210.c7},
  volume       = {65},
  year         = {2006},
}

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