Nucleolar dysfunction in Huntington's disease

Lee, Jung‐Hee; Hwang, Yu Jin; Ryu, Hwa-Sung; Kowall, Neil W.; Ryu, Hoon

doi:10.1016/j.bbadis.2013.09.017

Cited by 54 publications

(50 citation statements)

References 62 publications

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“…26 Finally, UBF is an important regulator of chromatin structure at the rDNA locus; it was shown to outcompete linker Histone H1 resulting in decondensation of rDNA chromatin. 17 Changes in chromatin status at the rDNA locus, coupled with nucleolar alterations, have been previously reported in Huntington disease [MIM 143100] 16 and were regulated by UBF post-translational modification by acetylation at Lys-352 and methylation at Lys-232. 16,27 The abnormally increased nucleolar size and reduced number of nucleoli per cell which was observed in the cells of the affected individual, suggest that the mutant hyperactive UBF causes an alteration in rDNA chromatin structure.…”

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confidence: 88%

“…17 Changes in chromatin status at the rDNA locus, coupled with nucleolar alterations, have been previously reported in Huntington disease [MIM 143100] 16 and were regulated by UBF post-translational modification by acetylation at Lys-352 and methylation at Lys-232. 16,27 The abnormally increased nucleolar size and reduced number of nucleoli per cell which was observed in the cells of the affected individual, suggest that the mutant hyperactive UBF causes an alteration in rDNA chromatin structure. Such a dysregulation would have a profound impact, since rDNA heterochromatin status is tightly regulated during differentiation and has a broader effect on heterochromatin formation throughout the nucleus.…”

mentioning

confidence: 88%

“…14 Increased rDNA expression is associated with chromatin decondensation at the rDNA locus and enlarged nucleoli. 15,16 We therefore checked whether the mutant UBF affects nucleolar architecture. Cells of an affected individual and control were methanol-fixed and subjected to immunofluorescence staining using antibodies recognizing the nucleolar marker nucleolin (Abcam ab50279).…”

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confidence: 99%

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Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood

Edvardson

Nicolae

Agrawal

et al. 2017

The American Journal of Human Genetics

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confidence: 99%

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Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood

Edvardson

Nicolae

Agrawal

et al. 2017

The American Journal of Human Genetics

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“…Huntington's Disease-Because nucleolar dysfunction is a feature of neurodegenerative diseases (12,16,17) and given that NPM1 is a key component of the nucleolus, we investigated…”

Section: Npm1 Is Up-regulated In the Striatum In Mouse Models Ofmentioning

confidence: 99%

“…Huntington's Disease-Because nucleolar dysfunction is a feature of neurodegenerative diseases (12,16,17) and given that NPM1 is a key component of the nucleolus, we investigated the status of NPM1 expression in mouse models of HD. 2 We first examined R6/2 transgenic mice, which are the most commonly used mouse model of HD (18,19).…”

Section: Npm1 Is Up-regulated In the Striatum In Mouse Models Ofmentioning

confidence: 99%

Regulation of Neuronal Survival by Nucleophosmin 1 (NPM1) Is Dependent on Its Expression Level, Subcellular Localization, and Oligomerization Status

Pfister

D’Mello

2016

Journal of Biological Chemistry

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NPM1 (nucleophosmin 1) is a nucleolar phosphoprotein that regulates many cellular processes, including ribosome biogenesis, proliferation, and genomic integrity. Although its role in proliferating cell types and tissues has been extensively investigated, little is known about its function in neurons and in the brain where it is highly expressed. We report that NPM1 protein expression is increased selectively in the striatum in both the R6/2 transgenic and 3-nitropropionic acid-injected mouse models of Huntington's disease. Examination of the effect of ectopic expression on cultured neurons revealed that increasing NPM1 is toxic to otherwise healthy cerebellar granule and cortical neurons. Toxicity is dependent on its cytoplasmic localization and oligomerization status. Forced retention of NPM1 in the nucleus, as well as inhibiting its ability to oligomerize, not only neutralizes NPM1 toxicity but also renders it protective against apoptosis. Although not blocked by pharmacological inhibition of the pro-apoptotic molecules, JNK, glycogen synthase kinase 3 beta, or caspases, toxicity is blocked by compounds targeting cyclin-dependent kinases (CDKs), as well as by dominant-negative forms of CDK1 and CDK2 and the pan-CDK inhibitor, p21Cip1/Waf1 . Although induced in in vivo Huntington's disease models, NPM1 protein levels are unchanged in cultured cerebellar granule and cortical neurons induced to die by low potassium or homocysteic acid treatment, respectively. Moreover, and counterintuitively, knockdown of its expression or inhibition of endogenous NPM1 oligomerization in these cultured neurons is toxic. Taken together, our study suggests that although neurons need NPM1 for survival, an increase in its expression beyond physiological levels and its translocation to the cytoplasm leads to death through abortive cell cycle induction.NPM1, also known as B23, is an abundant, ubiquitously expressed, and evolutionarily conserved non-ribosomal nucleolar phosphoprotein (1, 2). It is one of three members of the nucleophosmin/nucleoplasmin family of proteins, the other two being NPM2 and NPM3. NPM1 is an important regulator of a variety of cellular processes including centrosome duplication, genomic stability, cell proliferation, and the response to genotoxic stress. Inactivation of the NPM1 gene in mice causes death at midgestation, indicating its requirement for normal development. Fibroblasts cultured from NPM1 knock-out mice display genomic instability and reduced growth and cell proliferation (3). Other studies have shown that NPM1 can shuttle between the nucleolus and the nucleoplasm and from the nucleus to the cytoplasm. Nuclear export is believed to be required for cellular proliferation (4, 5). Mutations of NPM1 are associated with cancers and are responsible for approximately a third of cases of acute myeloid leukemia in humans (3, 6 -8). These mutations, which result in an altered C terminus containing an addition of a nuclear export signal, have been reported to aberrantly localize NPM1 to the cytoplasm (8). Ove...

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Green Fluorescent Protein Nanovessel Serves as a Nucleolus Targeting Material and Molecule Carrier in Living Cells

Shi

et al. 2019

Adv. Biosys.

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studied and widely used. Nonetheless, several drawbacks have been associated with these popular materials, such as complicated synthetic route, [34] high cost, [35] high cytotoxicity and low biocompatibility, [36] and difficulty in generalization and marketing. [37] On the other hand, among cell organelles, nucleolus plays a central role, which is localized in nucleus and responsible for RNA transcription, processing, and ribosome assembly. Recent research showed that nucleolus dysfunction was associated with a number of human diseases. [38][39][40][41] Hence, it is a critical task to develop tools for nucleolus imaging. Fluorescent probes exhibiting nucleolus precisely in living cells are particularly wanted, which are helpful for real-time monitoring the status of nucleolus under different conditions. However, this far most of available nucleolus targeting reagents are either antibodies against nucleolus proteins or overexpressed recombinant nucleolus proteins. [41] The former was very expensive and only suitable for the fixed cells, which excluded its use in living cells. The latter required sophisticated skill in molecular biology and was time-consuming. Apart from the above two options, the only commercially available nucleolus dye is SYTO RNA-Select (the only commercial dye with RNA targeting ability for nucleolus imaging). Notably, Wu and co-workers reported that certain fluorescent carbon quantum dots contained intrinsic nucleolus-targeting capability, suggesting new possibilities to develop materials for nucleolus imaging. [42] Recently, our laboratory has developed a fluorescent protein nanovessel (FPN) platform taking advantage of the supramolecular interaction between protein isomerization targeting (PIT) dyes and heated protein (e.g., bovine serum albumin (BSA)) scaffold. [43] This interaction turned on the fluorescence of PIT dyes, making these bio-abiotic hybrid materials a new organelle biomarker for living cells. Notably, PIT dyes are sensitive to various protein isomerization conditions such as protein fibrillation (unpublished data). As a new kind of bio-abiotic hybrid materials, FPNs are suitable for biological application and contain several advantages as compared to other regular biomaterials.In turn, we would like to know whether those well-known protein amyloid probes can be used as building blocks to construct FPNs. To this end, classic amyloid probe thioflavin T (ThT) was introduced into our test system. Notably, as a conventional dye, ThT has been used as an amyloid probe since 1959. This compound showed fluorescence signal when The nucleolus is responsible for RNA transcription, processing, and ribosome assembly, the dysfunction of which is associated with a number of diseases. In this report, a new member of fluorescent protein nanovessels (FPNs), constructed using thioflavin-T (ThT) and bovine serum albumin (BSA) as building blocks, is described. As a popular amyloid specific dye, ThT is nonfluorescent by itself, while its fluorescence can be lighted up upon interacting with amyloid ...

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Nucleolar dysfunction in Huntington's disease

Cited by 54 publications

References 62 publications

Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood

Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood

Regulation of Neuronal Survival by Nucleophosmin 1 (NPM1) Is Dependent on Its Expression Level, Subcellular Localization, and Oligomerization Status

Green Fluorescent Protein Nanovessel Serves as a Nucleolus Targeting Material and Molecule Carrier in Living Cells

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