Polyglutamine Expansion Reduces the Association of TATA-binding Protein with DNA and Induces DNA Binding-independent Neurotoxicity

Friedman, Meyer J.; Wang, Chuan-En; Li, Shengbo Eben

doi:10.1074/jbc.m709674200

Cited by 68 publications

(72 citation statements)

References 40 publications

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“…Under normal circumstances the inclusion bodies are present in the nucleus and cytoplasm; however, the expanded polyQ inclusion bodies tend to aggregate in the nucleus where they interfere with the transcriptional machinery (Lamark and Johansen 2012). In the present results, too, we find transcriptional repression of mdr49 and mdr50 following aggregation of polyQ in the nucleus, which is consistent with an earlier report of transcriptional repression of the MDR1 gene by expanded htt construct in human cell lines (Steffan et al 2000;Friedman et al 2008). Under normal circumstances, p53 represses MDR1; however, repression by mutant htt was found to be independent of p53 (Thottassery et al 1997), suggesting that expanded htt mediated transcriptional repression in a manner similar to p53.…”

supporting

confidence: 82%

“…However, in the presence of mutant polyQ, a nonactive form of b-catenin accumulates in the cytoplasm and polyQ aggregates enter the nucleus where it inhibits the transcription of mdr genes (Friedman et al 2008). This results in lowered P-gp transcription, which reduces P-gp in the membranes.…”

Section: Discussionmentioning

confidence: 99%

“…On the basis of these results, we propose a model ( Figure 10), which states that in a neuronal cell, under normal circumstances, b-catenin regulates transcription of P-gp, which results in accumulation of enough P-gp on the membrane to interact with actin as well as b-catenin. However, in the presence of mutant polyQ, a nonactive form of b-catenin accumulates in the cytoplasm and polyQ aggregates enter the nucleus where it inhibits the transcription of mdr genes (Friedman et al 2008). This results in lowered P-gp transcription, which reduces P-gp in the membranes.…”

mentioning

confidence: 99%

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Neurodegeneration Caused by Polyglutamine Expansion Is Regulated by P-Glycoprotein in Drosophila melanogaster

Yadav

Tapadia

2013

Genetics

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Trinucleotide CAG repeat disorders are caused by expansion of polyglutamine (polyQ) domains in certain proteins leading to fatal neurodegenerative disorders and are characterized by accumulation of inclusion bodies in the neurons. Clearance of these inclusion bodies holds the key to improve the disease phenotypes, which affects basic cellular processes such as transcription, protein degradation and cell signaling. In the present study, we show that P-glycoprotein (P-gp), originally identified as a causative agent of multidrug-resistant cancer cells, plays an important role in ameliorating the disease phenotype. Using a Drosophila transgenic strain that expresses a stretch of 127 glutamine repeats, we demonstrate that enhancing P-gp levels reduces eye degeneration caused by expression of polyQ, whereas reducing it increases the severity of the disease. Increase in polyQ inclusion bodies represses the expression of mdr genes, suggesting a functional link between P-gp and polyQ. P-gp up-regulation restores the defects in the actin organization and precise array of the neuronal connections caused by inclusion bodies. b-Catenin homolog, Armadillo, also interacts with P-gp and regulates the accumulation of inclusion bodies. These results thus show that P-gp and polyQ interact with each other, and changing P-gp levels can directly affect neurodegeneration.T HE polyglutamine (polyQ) expansion neurodegenerative diseases are characterized by the increase in CAG trinuleotide repeats in diseased genes. Nine diseases, including Huntington's and several spinocerebellar ataxias, have been identified so far, which result from accumulation of insoluble mutant proteins, making the neurons vulnerable to degeneration in specific regions of the brain (Mattson and Magnus 2006). It is still not known why only a specific population of neurons is affected, though these aggregates are widely expressed in the central nervous system (Welch and Diamond 2001;Michalik and Broeckhoven 2003). The onset of disease is by the accumulation of intracellular inclusion bodies formed due to gain of function of misfolded protein aggregates (Ross and Poirier 2004). The mutant polyQ peptide monomers are soluble in nature but they have a natural tendency to associate with each other and form insoluble aggregates either in neurons or in extracellular regions (Di Figlia et al. 1997;Ross and Poirier 2004;Bossy et al. 2008;Takahashi et al. 2008). The onset and severity of the disease is directly proportional to the length of polyQ tracts (Legleiter et al. 2010).The expanded polyQ proteins exhibit more stability and evade degradation by proteosome machinery and the disease progression is due to imbalance between accumulation and clearance of the aggregates (Verhoef et al. 2002;Matus et al. 2008). However in neurodegenerative diseases, stress caused by misfolded proteins, damage the ubiquitinproteosome system, which leads to defects in clearance of inclusion bodies (Matus et al. 2008;Riederer et al. 2011). The pathogenic conditions could also be because...

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supporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Neurodegeneration Caused by Polyglutamine Expansion Is Regulated by P-Glycoprotein in Drosophila melanogaster

Yadav

Tapadia

2013

Genetics

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“…Furthermore, over-expression of TFIIB and HSPB1 rescued neurodegeneration [56]. It has also been shown that the mutant TBP in transgenic mouse binds to promoter DNA [57].…”

Section: )Spinocerebellarataxiatype17(sca17)mentioning

confidence: 96%

Unstable Repeat Expansion in Neurodegenerative Dementias: Mechanisms of Disease

Yang

Seol

2012

Dement Neurocognitive Disord

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The majority of neurodegenerative dementias are thought to result primarily from the misfolding, aggregation and accumulation of proteins which interfere with protein homeostasis in the brain. Some of them are caused by the expansion of unstable nucleotide repeats, which include Huntington's disease as a prototype. Other neurodevelopmental or neurodegenerative disorders, such as fragile X syndrome, some spinocerebellar ataxias and myotonic dystrophies exhibit cognitive or behavioral deficits as parts of their clinical manifestations. Unstable repeat expansions include trinucleotide, tetranucleotide, and pentanucleotide. Recently hexanucleotide repeat expansion in frontotemporal dementia and amyotrophic lateral sclerosis was identified. The pathogenic mechanisms for these repeat disorders include either loss of protein function or gain of function at the protein or RNA levels. The aim of this article is to review proposed mechanisms by which unstable repeat expansions give rise to degeneration of brain with the hope of understanding the diseases and providing insights into the areas of therapeutic intervention. We will review these potential mechanisms in the context of fragile X syndrome, Huntington's disease, spinocerebellar ataxias, myotonic dystrophy, and frontotemporal dementia and amyotrophic lateral sclerosis. We will also discuss the potential targets for therapeutic intervention.

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“…TBP, the protein involved in SCA17, is an essential component of the transcriptional initiation complex [191], directing it to DNA via binding to the TATA-box [192]. Studies with SCA17 transgenic mice indicate that polyQ expansion in TBP alters its ability to bind DNA and transcriptional regulators, suggesting that transcriptional dysregulation contributes to SCA17 pathogenesis [193][194][195][196]. In SCA17, mutant TBP accumulates in intranuclear aggregates [190].…”

Section: Spinocerebellar Ataxias and Dentatorubral-pallidoluysian Atrmentioning

confidence: 99%

Modulation of Molecular Chaperones in Huntington’s Disease and Other Polyglutamine Disorders

2016

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Polyglutamine expansion mutations in specific proteins underlie the pathogenesis of a group of progressive neurodegenerative disorders, including Huntington's disease, spinal and bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, and several spinocerebellar ataxias. The different mutant proteins share ubiquitous expression and abnormal proteostasis, with misfolding and aggregation, but nevertheless evoke distinct patterns of neurodegeneration. This highlights the relevance of the full protein context where the polyglutamine expansion occurs, and suggests different interactions with the cellular proteostasis machinery. Molecular chaperones are key elements of the proteostasis machinery and therapeutic targets for neurodegeneration. Here we provide a focused review on Hsp90, Hsp70, and their cochaperones, and how their genetic or pharmacological modulation affects the proteostasis and disease phenotypes in cellular and animal models of polyglutamine disorders. The emerging picture is that, in principle, Hsp70 modulation may be more amenable for long-term treatment by promoting a more selective clearance of mutant proteins than Hsp90 modulation, which may further decrease the necessary wild-type counterparts. It seems, nevertheless, unlikely that a single Hsp70 modulator will benefit all polyglutamine diseases. Indeed, available data, together with insights from effects on tau and alpha-synuclein in models of Alzheimer's and Parkinson's diseases, indicates that Hsp70 modulators may lead to different effects on the proteostasis of different mutant and wild-type client proteins. Future studies should include the further development of isoform selective inhibitors, namely to avoid off-target effects on Hsp in the mitochondria, and their characterization in distinct polyglutamine disease models to account for client protein-specific differences.

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Polyglutamine Expansion Reduces the Association of TATA-binding Protein with DNA and Induces DNA Binding-independent Neurotoxicity

Cited by 68 publications

References 40 publications

Neurodegeneration Caused by Polyglutamine Expansion Is Regulated by P-Glycoprotein in Drosophila melanogaster

Neurodegeneration Caused by Polyglutamine Expansion Is Regulated by P-Glycoprotein in Drosophila melanogaster

Unstable Repeat Expansion in Neurodegenerative Dementias: Mechanisms of Disease

Modulation of Molecular Chaperones in Huntington’s Disease and Other Polyglutamine Disorders

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