Intranuclear Neuronal Inclusions in Huntington's Disease and Dentatorubral and Pallidoluysian Atrophy: Correlation between the Density of Inclusions andIT15CAG Triplet Repeat Length

Bêcher, Mark W.; Kotzuk, Joyce A.; Sharp, Alan H.; Davies, Stephen; Bates, Gillian P.; Price, Donald L.; Ross, Christopher A.

doi:10.1006/nbdi.1998.0168

Cited by 398 publications

(261 citation statements)

References 50 publications

Supporting

Mentioning

248

Contrasting

Unclassified

Order By: Relevance

“…In some of the diseases, inclusions have been observed in the cytoplasm, dendrites, and axonal processes. The inclusions are generally seen in affected areas of the brain (7,8), though not limited to those neurons most likely to degenerate (9). Thus, whether inclusions are responsible for neurotoxicity has been controversial.…”

mentioning

confidence: 99%

Polyglutamine fibrillogenesis: The pathway unfolds

Ross

Poirier

Wanker

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

122

View full text Add to dashboard Cite

mentioning

confidence: 99%

Polyglutamine fibrillogenesis: The pathway unfolds

Ross

Poirier

Wanker

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

122

View full text Add to dashboard Cite

“…Therefore, the subcellular localization of the 771-15 proteins does not in£uence their toxicity. In addition, there was a signi¢cant decrease in cell death associated with expression of the 771-15 proteins compared with the 771-128 proteins (p 5 0.001, n 5), as Becher et al 1998;Gour¢nkel-An et al 1998), and mice transgenic for huntingtin exon 1 develop nuclear aggregates prior to the onset of debilitating neurological symptoms . Furthermore, increasing toxicity of successively smaller huntingtin fragments in our cell culture model was associated with the formation of nuclear aggregates (Hackam et al 1998a).…”

Section: Resultsmentioning

confidence: 90%

“…S. Hackam, unpublished observations). Furthermore, as observed in post-mortem neocortical tissue (Becher et al 1998), increasing polyglutamine length is associated with an increased frequency of aggregates in vitro (Martindale et al 1998;Lunkes & Mandel 1998). More severe grades of HD have a higher frequency of cortical nuclear inclusions (Becher et al 1998).…”

Section: (B) the Cell Culture Model Can Mimic In Vivo Eventsmentioning

confidence: 96%

“…Aggregates were present in the dentate nucleus of the cerebellum in HD patients (Becher et al 1998), an area that does not frequently exhibit neurodegeneration. Intranuclear inclusions were also identi¢ed in SCA-7 (Holmberg et al 1998) and DRPLA (Becher et al 1998) patients in regions of the brain not a¡ected by the disease. Ubiquitinated intranuclear inclusions formed by mutant androgen receptor aggregates were observed in SMBA patients in peripheral tissues .…”

Section: (B) the Cell Culture Model Can Mimic In Vivo Eventsmentioning

confidence: 97%

See 1 more Smart Citation

Evidence for both nucleus and cytoplasm as subcellular sites of pathogenesis in Huntington'sdisease in cell culture and in transgenic mice expressing mutant huntingtin

Hackam

Hodgson

Singaraja

et al. 1999

Phil. Trans. R. Soc. Lond. B

View full text Add to dashboard Cite

A unifying feature of the CAG expansion diseases is the formation of intracellular aggregates composed of the mutant polyglutamine-expanded protein. Despite the presence of aggregates in a¡ected patients, the precise relationship between aggregates and disease pathogenesis is unresolved. Results from in vivo and in vitro studies of mutant huntingtin have led to the hypothesis that nuclear localization of aggregates is critical for the pathology of Huntington's disease (HD). We tested this hypothesis using a 293T cell culture model system by comparing the frequency and toxicity of cytoplasmic and nuclear huntingtin aggregates. Insertion of nuclear import or export sequences into huntingtin fragments containing 548 or 151 amino acids was used to reverse the normal localization of these proteins. Changing the subcellular localization of the fragments did not in£uence their total aggregate frequency. There were also no signi¢cant di¡erences in toxicity associated with the presence of nuclear compared with cytoplasmic aggregates. These studies, together with ¢ndings in transgenic mice, suggest two phases for the pathogenesis of HD, with the initial toxicity in the cytoplasm followed by proteolytic processing of huntingtin, nuclear translocation with increased nuclear concentration of N-terminal fragments, seeding of aggregates and resultant apoptotic death. These ¢ndings support the nucleus and cytosol as subcellular sites for pathogenesis in HD.

show abstract

“…However, the intranuclear inclusions have shown immunoreactivity associated only with epitopes in the furthermost N-teminal regions of huntingtin, the region within which the polyglutamine sequence resides Becher et al 1998). Antibodies detecting more C-terminal epitopes of huntingtin have not been localized to inclusions.…”

Section: Introductionmentioning

confidence: 99%

The localization and interactions of huntingtin

1999

Phil. Trans. R. Soc. Lond. B

View full text Add to dashboard Cite

Huntingtin was localized by using a series of antibodies that detected di¡erent areas of the protein from the immediate N-terminus to the C-terminal region of the protein. The more C-terminal antibodies gave a cytoplasmic localization in neurons of the brain in controls and cases of Huntington's disease (HD). The N-terminal antibody, however, gave a distinctive pattern of immunoreactivity in the HD brain, with marked staining of axon tracts and white matter and the detection of densely staining intranuclear inclusions. This implies some processing di¡erences between mutated and normal huntingtin. We have also localized two interacting proteins, cystathionine b-synthase and the nuclear receptor co-repressor (N-CoR), in brain. Cystathionine b-synthase was not relocalized in HD brain, but the N-CoR was excluded from neuronal nuclei in HD brain, and a further protein that exists in the same repression complex, mSin3, was similarly excluded. We conclude that the co-repressor might have a part in HD pathology.

show abstract

Intranuclear Neuronal Inclusions in Huntington's Disease and Dentatorubral and Pallidoluysian Atrophy: Correlation between the Density of Inclusions andIT15CAG Triplet Repeat Length

Cited by 398 publications

References 50 publications

Polyglutamine fibrillogenesis: The pathway unfolds

Polyglutamine fibrillogenesis: The pathway unfolds

Evidence for both nucleus and cytoplasm as subcellular sites of pathogenesis in Huntington'sdisease in cell culture and in transgenic mice expressing mutant huntingtin

The localization and interactions of huntingtin

Contact Info

Product

Resources

About