Search results for "binding"
showing 10 items of 3896 documents
Genetic and Chemical Modifiers Of A CUG Toxicity Model in Drosophila
2007
Non-coding CUG repeat expansions interfere with the activity of human Muscleblind-like (MBNL) proteins contributing to myotonic dystrophy 1 (DM1). To understand this toxic RNA gain-of-function mechanism we developed a Drosophila model expressing 60 pure and 480 interrupted CUG repeats in the context of a non-translatable RNA. These flies reproduced aspects of the DM1 pathology, most notably nuclear accumulation of CUG transcripts, muscle degeneration, splicing misregulation, and diminished Muscleblind function in vivo. Reduced Muscleblind activity was evident from the sensitivity of CUG-induced phenotypes to a decrease in muscleblind genetic dosage and rescue by MBNL1 expression, and furthe…
Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules.
2004
AbstractPolyglutamine expansion (polyQ) in the protein huntingtin is pathogenic and responsible for the neuronal toxicity associated with Huntington's disease (HD). Although wild-type huntingtin possesses antiapoptotic properties, the relationship between the neuroprotective functions of huntingtin and pathogenesis of HD remains unclear. Here, we show that huntingtin specifically enhances vesicular transport of brain-derived neurotrophic factor (BDNF) along microtubules. Huntingtin-mediated transport involves huntingtin-associated protein-1 (HAP1) and the p150Glued subunit of dynactin, an essential component of molecular motors. BDNF transport is attenuated both in the disease context and b…
Huntingtin mediates dendritic transport of β-actin mRNA in rat neurons
2011
Transport of mRNAs to diverse neuronal locations via RNA granules serves an important function in regulating protein synthesis within restricted sub-cellular domains. We recently detected the Huntington's disease protein huntingtin (Htt) in dendritic RNA granules; however, the functional significance of this localization is not known. Here we report that Htt and the huntingtin-associated protein 1 (HAP1) are co-localized with the microtubule motor proteins, the KIF5A kinesin and dynein, during dendritic transport of β-actin mRNA. Live cell imaging demonstrated that β-actin mRNA is associated with Htt, HAP1, and dynein intermediate chain in cultured neurons. Reduction in the levels of Htt, H…
In vivo discovery of a peptide that prevents CUG-RNA hairpin formation and reverses RNA toxicity in myotonic dystrophy models
2011
6 pages, 5 figures. PMID:21730182[PubMed] PMCID: PMC3141925[Available on 2012/1/19]
Correction: Daunorubicin reduces MBNL1 sequestration caused by CUG-repeat expansion and rescues cardiac dysfunctions in a Drosophila model of myotoni…
2018
ABSTRACT Myotonic dystrophy (DM) is a dominantly inherited neuromuscular disorder caused by expression of mutant myotonin-protein kinase (DMPK) transcripts containing expanded CUG repeats. Pathogenic DMPK RNA sequesters the muscleblind-like (MBNL) proteins, causing alterations in metabolism of various RNAs. Cardiac dysfunction represents the second most common cause of death in DM type 1 (DM1) patients. However, the contribution of MBNL sequestration in DM1 cardiac dysfunction is unclear. We overexpressed Muscleblind (Mbl), the Drosophila MBNL orthologue, in cardiomyocytes of DM1 model flies and observed a rescue of heart dysfunctions, which are characteristic of these model flies and resem…
Deregulated Splicing Is a Major Mechanism of RNA-Induced Toxicity in Huntington's Disease.
2019
Huntington's disease (HD) is caused by an expanded CAG repeat in the huntingtin (HTT) gene, translating into an elongated polyglutamine stretch. In addition to the neurotoxic mutant HTT protein, the mutant CAG repeat RNA can exert toxic functions by trapping RNA-binding proteins. While few examples of proteins that aberrantly bind to mutant HTT RNA and execute abnormal function in conjunction with the CAG repeat RNA have been described, an unbiased approach to identify the interactome of mutant HTT RNA is missing. Here, we describe the analysis of proteins that preferentially bind mutant HTT RNA using a mass spectrometry approach. We show that (I) the majority of proteins captured by mutant…
An efficient Escherichia coli expression system for the production of a functional N-terminal domain of the T1R3 taste receptor.
2012
http://www.landesbioscience.com/; International audience; Sweet taste is mediated by a dimeric receptor composed of two distinct subunits, T1R2 and T1R3, whereas the T1R1/T1R3 receptor is involved in umami taste perception. The T1R1, T1R2, and T1R3 subunits are members of the small family of class C G protein-coupled receptors (GPCRs). The members of this family are characterized by a large N-terminal domain (NTD), which is structurally similar to bacterial periplasmic-binding proteins and contains the primary ligand-binding site. In a recent study, we described a strategy to produce a functional dimeric human T1R3-NTD. Although the protein was expressed as inclusion bodies (IBs) using the …
Substrate specificity overlap and interaction between Adrenoleukodystrophy protein (ALDP/ABCD1) and Adrenoleukodystrophy-related protein (ALDRP/ABCD2)
2011
X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder caused by mutations in the ABCD1 gene, which encodes a peroxisomal member of the ATP-binding cassette (ABC) transporter subfamily D called ALDP. ALDP is supposed to function as a homodimer allowing the entry of CoA-esters of very-long chain fatty acids (VLCFA) into the peroxisome, the unique site of their β-oxidation. ALDP deficiency can be corrected by overexpression of ALDRP, its closest homolog. However, the exact nature of the substrates transported by ALDRP and its relationships with ALDP still remain unclear. To gain insight into the function of ALDRP, we used cell models allowing the induction in a dose-dependent m…
Evidence of oxidative stress in very long chain fatty acid--treated oligodendrocytes and potentialization of ROS production using RNA interference-di…
2011
X-linked adrenoleukodystrophy (X-ALD) and pseudo neonatal adrenoleukodystrophy (P-NALD) are neurodegenerative demyelinating diseases resulting from the functional loss of the peroxisomal ATP-binding cassette transporter D (ABCD1) and from single peroxisomal enzyme deficiency (Acyl-CoA oxidase1: ACOX1), respectively. As these proteins are involved in the catabolism of very long chain fatty acids (VLCFA: C24:0, C26:0), X-ALD and P-NALD patients are characterized by the accumulation of VLCFA in plasma and tissues. Since peroxisomes are involved in the metabolism of reactive oxygen species (ROS) and nitrogen species (RNS), we examined the impact of VLCFA on the oxidative status of 158N murine o…
Reliable Correlational Cuing While Controlling for Most-Recent-Pairing Effects.
2020
Irrelevant aspects of the environment or irrelevant attributes of task-relevant stimuli can have important and reliable effects on behavior. When the specific values of an irrelevant stimulus attribute are correlated with different responses, a correlational-cuing effect is observed: faster and more accurate responses when the correlation is positive than when it is negative. Previous work has shown that this effect is not due to simple differences in how often the specific stimuli are being presented, and most explanations of the effect have stressed the clear parallels with classical associative learning. Very recently, however, evidence in favor of an alternative model has been presented…