Myricetin Reduces Toxic Level of CAG Repeats RNA in Huntington ’s Disease (HD) and Spino Cerebellar Ataxia (SCAs)

ACS Chemical BiologyDOI: 10.1021/acschembio.7b00699
Source: ACS Chemical Biology - Category: Chemistry Authors: Source Type: research

Related Links:

Abstract Expansions of simple trinucleotide repeats, such as (CGG)n, (CAG)n or (GAA)n, are responsible for more than 40 hereditary disorders in humans including fragile X syndrome, Huntington's disease, myotonic dystrophy, and Friedreich's ataxia. While the mechanisms of repeat expansions were intensively studied for over two decades, the final picture has yet to emerge. It was important, therefore, to develop a mammalian experimental system for studying repeat instability, which would recapitulate repeat instability observed in human pedigrees. Here, we describe a genetically tractable experimental system to stud...
Source: Mol Biol Cell - Category: Molecular Biology Authors: Tags: Methods Mol Biol Source Type: research
We describe a general strategy for the construction of clonal cell lines containing CNG repeats of various lengths, in which the microsatellites are integrated using the yeast FLP recombinase at a single ectopic recombination acceptor site in the HeLa genome. We illustrate two types of (CTG/CAG) cell lines, one of which contains dual fluorescent marker genes flanking the (CTG/CAG) repeat, and one which does not. We show that long CNG repeats are prone to DNA double strand breaks (DSBs) upon exposure of these cell lines to prolonged replication stress. PMID: 31586345 [PubMed - in process]
Source: Mol Biol Cell - Category: Molecular Biology Authors: Tags: Methods Mol Biol Source Type: research
AbstractSpinocerebellar ataxia type 3, or Machado –Joseph disease (SCA3/MJD), is caused by an expansion of CAG repeats, which is inversely correlated to age at onset (AO) of symptoms. However, on average, just 55.2% of variation in AO can be explained by expansion length. Additional modulators, such as polymorphic CAG tract inATXN2 gene, can raise to 63.0% of the variation in AO. A sequence variation (rs3512) inFAN1 gene has previously been shown to be associated with late AO in Huntington ’s disease and polyglutaminopathies associated to ataxia. In the present study, genotype frequency of rs3512 was demonstrat...
Source: NeuroMolecular Medicine - Category: Neurology Source Type: research
Shulman Liu Target nomination for drug development has been a major challenge in the path to finding a cure for several neurological disorders. Comprehensive transcriptome profiles have revealed brain gene expression changes associated with many neurological disorders, and the functional validation of these changes is a critical next step. Model organisms are a proven approach for the elucidation of disease mechanisms, including screening of gene candidates as therapeutic targets. Frequently, multiple models exist for a given disease, creating a challenge to select the optimal model for validation and functional fo...
Source: Genes - Category: Genetics & Stem Cells Authors: Tags: Article Source Type: research
AbstractRecent genome-wide association studies of Huntington ’s disease (HD) primarily highlighted genes involved in DNA damage repair mechanisms as modifiers of age at onset and disease severity, consistent with evidence that more DNA repair genes are being implicated in late age–onset neurodegenerative diseases. This provides an exciting opportunity to advance therapeutic development in HD, as these pathways have already been under intense investigation in cancer research. Also emerging are the roles of other polyglutamine disease proteins in DNA damage repair mechanisms. A potential universal trigger of oxid...
Source: Neurotherapeutics - Category: Neurology Source Type: research
Abstract DNA double-strand breaks (DSBs) are common events that were recognized as one of the most toxic lesions in eukaryotic cells. DSBs are widely involved in many physiological processes such as V(D)J recombination, meiotic recombination, DNA replication and transcription. Deregulation of DSBs has been reported in multiple diseases in human beings such as the neurodegenerative diseases, with which the underlying mechanisms are needed to be illustrated. Here, we reviewed the recent insights into dysfunction of DSB formation and repair contributing to the pathogenesis of neurodegenerative disorders including Alz...
Source: Current Neuropharmacology - Category: Drugs & Pharmacology Authors: Tags: Curr Neuropharmacol Source Type: research
CONCLUSIONS: All patients reported a communication complaint, attested by the DIP scores, despite the fact that not all patients, notably PD, ataxic, and PSP patients, had an intelligibility deficit. The DIP should be used in clinical practice to contribute to a holistic evaluation and management of functional communication in patients with dysarthria. PMID: 31112944 [PubMed - as supplied by publisher]
Source: Neuro-Degenerative Diseases - Category: Neurology Authors: Tags: Neurodegener Dis Source Type: research
AbstractNucleotide repeat disorders encompass more than 30 diseases, most of which show dominant inheritance, such as Huntington ’s disease, spinocerebellar ataxias, and myotonic dystrophies. Yet others, including Friedreich’s ataxia, are recessively inherited. A common feature is the presence of a DNA tandem repeat in the disease-associated gene and the propensity of the repeats to expand in germ and in somatic cells, wi th ensuing neurological and frequently also neuromuscular defects. Repeat expansion is the most frequent event in these diseases; however, sequence contractions, deletions, and mutations have ...
Source: Neurotherapeutics - Category: Neurology Source Type: research
Abstract Huntington's diseases (HD) is a very devastating disease caused by r(CAG) expansion in HTT gene, encoding the huntingtin protein. r(CAG) expansion causes disease via multiple pathways including, 1) loss of normal protein function like sequestration of RNA binding protein such as Muscleblind-like (MBNL) and nucleolin, 2) Gain of function for mutant proteins and 3) repeat-associated non-ATG (RAN) translation; in which expanded r(CAG) translates into toxic poly glu, poly ser, or poly ala without the use of any canonical start codon. Herein, we have rationally designed and synthesized a unique class of pyrido...
Source: Biochimie - Category: Biochemistry Authors: Tags: Biochimie Source Type: research
Purpose of review Anti-IgLON5 disease is a novel entity characterized by a distinctive sleep disorder associated with a variety of neurological symptoms, antibodies against IgLON5, and pathological findings of neuronal tauopathy. The characteristic sleep disorder occurs in most patients, but other neurological symptoms are also important because they can be the presenting and most disabling problem and mimic other conditions. This review focuses on nonsleep neurological symptoms and presentations of anti-IgLON5 disease. Recent findings Apart from sleep problems, the most frequent neurological symptoms in anti-IgLON5 d...
Source: Current Opinion in Neurology - Category: Neurology Tags: WIDENING SPECTRUM OF CNS INFLAMMATORY DISORDERS OF THE CNS: Edited by Francesc Graus Source Type: research
More News: Ataxia | Biology | Chemistry | Huntington's Disease | Toxicology