Disease relevance of Intranuclear Inclusion Bodies

• These cleavage sites or gene product boundaries are defined by the heptapeptide sequence...Glu-Xaa-Xaa-Tyr-Xaa-Gln-Ser or Gly.... We have used the 54 kd Mr nuclear inclusion protein/30 kd Mr capsid protein junction as a model to examine the role of these conserved amino acids in defining a cleavage site [1].
• Routine hematoxylin and eosin staining of esophageal mucosal and submucosal specimens showed intranuclear inclusions in all patients, whereas cytomegalovirus culture was positive in only 8 of 14 patients [2].
• The discovery last year of neuronal intranuclear inclusions in Huntington's disease and other disorders with expanded glutamine repeats has suggested a unifying mechanism underlying the pathogenesis of this class of neurodegenerative diseases [3].
• Electron microscopy revealed extravasation of HRP between endothelial cells, intranuclear inclusions characteristic of lead poisoning in Schwann cell nuclei, demyelination, and remyelination [4].
• Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) is characterized pathologically by intranuclear inclusions in skeletal muscles and is caused by the expansion of a 10-alanine stretch to 12-17 alanines in the intranuclear poly(A)-binding protein 2 (PABP2) [5].

Psychiatry related information on Intranuclear Inclusion Bodies

• The protein huntingtin (htt), aggregated in neuronal nuclear inclusions, is pathognomonic of Huntington's disease (HD) [6].
• We demonstrate that mutant VCP causes a novel type of frontotemporal dementia characterized by neuronal nuclear inclusions containing ubiquitin and VCP [7].

High impact information on Intranuclear Inclusion Bodies

• Expanded polyglutamine proteins form aggregates, including nuclear inclusions (NI), within neurons, possibly due to misfolding of the proteins [8].
• Blocking nuclear localization of mutant huntingtin suppressed its ability to form intranuclear inclusions and to induce neurodegeneration [9].
• Nuclear inclusions in glutamine repeat disorders: are they pernicious, coincidental, or beneficial [10]?
• Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation [11].
• Neurons that appeared most vulnerable had relatively high levels of mutant ataxin-7; it is interesting, however, that marked dysfunction occurred in these neurons weeks prior to the appearance of nuclear inclusions [12].

Chemical compound and disease context of Intranuclear Inclusion Bodies

• Neuronal intranuclear inclusions are found in the brains of patients with Huntington's disease and form from the polyglutamine-expanded N-terminal region of mutant huntingtin [13].
• Creatine lessened brain atrophy and the formation of intranuclear inclusions, attenuated reductions in striatal N-acetylaspartate as assessed by NMR spectroscopy, and delayed the development of hyperglycemia [14].
• These intranuclear inclusions demonstrated positive immunostaining for biotin using the peroxidase-antiperoxidase method in all but six cases, whereas there was no reaction for Herpes simplex in any of the cases [15].
• This experiment demonstrates that nuclear inclusion bodies formed in lead poisoning are disrupted and removed from the nuclei by the administration of EDTA [16].
• The gene encoding the C-terminal protease domain (27 kDa) of the nuclear inclusion protein a of turnip mosaic potyvirus C5 was cloned and expressed as a fusion protein with glutathione S-transferase in Escherichia coli XL1-blue [17].

Biological context of Intranuclear Inclusion Bodies

• However, intranuclear inclusions may reflect a cellular mechanism to protect against huntingtin-induced cell death [9].
• Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions [18]?
• Pathogenesis in HD seems to involve the formation of neuronal intranuclear inclusions and the abnormal regulation of transcription and signal transduction [19].
• Lack of phosphorylation of arfaptin 2 at this site substantially modified its subcellular distribution and increased neuronal death and intranuclear inclusions caused by polyQ-huntingtin [20].
• In previous work, we have shown that the protease domain of the nuclear inclusion a protease (NIaPro) from PVY is the elicitor of the Ry-mediated resistance and that integrity of the protease active site is required for the elicitation of the resistance response [21].

Anatomical context of Intranuclear Inclusion Bodies

• A more truncated N-terminal fragment of huntingtin is also produced, that appears involved in building up cytoplasmic inclusions at early time points, and later on also nuclear inclusions [22].
• This resulted in formation of nuclear inclusions, progressive decrease in dEAAT1 transcription and shortened adult lifespan, but no significant glial cell death [23].
• Ataxin-7 colocalizes with full-length R85 (R85FL) in co-transfected Cos-7 cells and with one of the SH3P12GPs in neuronal intranuclear inclusions in brain from a SCA7 patient [24].
• Although some CBP staining appeared as dots in the selective brain regions (e.g. hypothalamus and amygdala), double labeling showed that most CBP was not co-localized with huntingtin nuclear inclusions [25].
• In the motor neurons of SBMA patients, there were AR-immunoreactive ubiquitinated nuclear inclusions that were detected by antibodies that recognize a small portion of the N terminus of the AR protein [26].

Associations of Intranuclear Inclusion Bodies with chemical compounds

• Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila [27].
• We have identified a novel guanosine triphosphatase (GTPase) named CRAG that contains a nuclear localization signal (NLS) sequence and forms nuclear inclusions in response to stress [28].
• These data provide the first physiological evidence that polyalanine expansions are not essential to induce polymerization of PABPN1 into filamentous nuclear inclusions [29].
• However, two mutant isoforms, R256C and R275W, within RING finger 1 of the Parkin protein (238-293 amino acids), produced an unusual distribution of the protein, with large cytoplasmic and nuclear inclusions [30].
• Extrapolating from TEM to standard light microscopy on hematoxylin and eosin-stained paraffin sections, eosinophilic, targetoid intranuclear inclusions were identified within spindle cells which often lined vascular lumina [31].

Gene context of Intranuclear Inclusion Bodies

• Neuronal intranuclear inclusions and cytoplasmic aggregates composed of the mutant huntingtin within certain neuronal populations are a characteristic hallmark of HD [32].
• However, in 293 cells HHR23A is recruited to intranuclear inclusions formed by the mutant ataxin-3 through its interaction with ataxin-3 [33].
• Neuronal intranuclear inclusions were detected in the brain of an early onset SCA7 case with the 1C2 antibody directed against an expanded polyglutamine domain [34].
• FXTAS is thought to be caused by a toxic 'gain-of-function' of the expanded CGG-repeat FMR1 mRNA, which is found in the neuronal and astrocytic intranuclear inclusions associated with the disorder [35].
• The observations in expanded-repeat mice support a direct role of the Fmr1 gene, by either CGG expansion per se or by mRNA level, in the formation of the inclusions and suggest a correlation between the presence of intranuclear inclusions in distinct regions of the brain and the clinical features in symptomatic premutation carriers [36].

Analytical, diagnostic and therapeutic context of Intranuclear Inclusion Bodies

• We also show CBP incorporation into nuclear inclusions formed in a cell culture model of another polyglutamine disease, spinocerebellar ataxia type 3 [37].
• All four patients with BKVAN demonstrated intranuclear inclusions on allograft biopsy and a progressive rise in serum creatinine; three patients underwent multiple biopsies before the diagnosis of BKVAN was made [38].
• The sera cross-reacted an estimated 10% with HCMV DB140 in an indirect immunoassay, and their use in immunofluorescence localized DB140 to the nuclear inclusions of HCMV-infected cells [39].
• Using immunohistochemistry, we show here that ubiquitinated intranuclear inclusions are also observed postmortem in the brain of patients suffering from Huntington's disease characterized by small polyglutamine expansions and adult onset [40].
• Triple-labeling immunofluorescence revealed that ataxin-2, expanded polyglutamine and ubiquitin were colocalized to these neuronal intranuclear inclusions (NIs), indicating that SCA2 shares morphological characteristics common to other neurological disorders associated with an expansion of CAG/polyglutamine-repeat [41].

References