Article

Trinucleotide repeat disorders.

Institute of Human Genetics, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Annual Review of Neuroscience (Impact Factor: 22.66). 02/2007; 30:575-621. DOI: 10.1146/annurev.neuro.29.051605.113042
Source: PubMed

ABSTRACT The discovery that expansion of unstable repeats can cause a variety of neurological disorders has changed the landscape of disease-oriented research for several forms of mental retardation, Huntington disease, inherited ataxias, and muscular dystrophy. The dynamic nature of these mutations provided an explanation for the variable phenotype expressivity within a family. Beyond diagnosis and genetic counseling, the benefits from studying these disorders have been noted in both neurobiology and cell biology. Examples include insight about the role of translational control in synaptic plasticity, the role of RNA processing in the integrity of muscle and neuronal function, the importance of Fe-S-containing enzymes for cellular energy, and the dramatic effects of altering protein conformations on neuronal function and survival. It is exciting that within a span of 15 years, pathogenesis studies of this class of disorders are beginning to reveal pathways that are potential therapeutic targets.

3 Followers
 · 
181 Views
  • Source
    [Show description] [Hide description]
    DESCRIPTION: Contribution for a book entitled: Myotonic Dystrophies: Epidemiology, Diagnosis and Therapeutic Challenges.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This chapter addresses novel interesting findings of therapeutic potential to target DM1 with small molecule kinase inhibitors and the promises this may provide to this devastating disorder. DM1 is the most common muscular dystrophy in adults and at present has no effective therapy for its treatment. The pathogenesis of this autosomal dominant disorder is mediated by the mutant transcript. DMPK transcripts with expanded CUG repeats (CUG mut) become arrested in the nucleus and form multiple discrete inclusions (foci), and their toxic effects are mediated through at least two antagonistic regulators of alternative splicing: MBNL1 and CUGBP1. Loss of MBNL1 and a gain of CUGBP1 functions result in aberrant splicing of several mRNAs which lead to predominance of embryonic-specific splicing isoforms in adult DM1 tissues. To date, efforts to develop therapeutic strategies for DM1 have mostly been focused on disrupting the toxic nuclear foci by targeting CUG mut with antisense tools. However, the latest reports provide evidence for a novel alternative strategy via targeting protein kinases with small molecule inhibitors. There is reason to envisage such an approach since in DM1 cells CUG mut adversely affect various proteomic elements. As
    Myotonic Dystrophies: Epidemiology, Diagnosis and Therapeutic Challenges, 01/2015; NOVA SCIENCE PUBLISHERS, INC..
  • [Show abstract] [Hide abstract]
    ABSTRACT: Trinucleotide repeat expansion disorders (TREDs) are a group of dominantly inherited neurological diseases caused by the expansion of unstable repeats in specific regions of the associated genes. Expansion of CAG repeat tracts in translated regions of the respective genes results in polyglutamine- (polyQ-) rich proteins that form intracellular aggregates that affect numerous cellular activities. Recent evidence suggests the involvement of an RNA toxicity component in polyQ expansion disorders, thus increasing the complexity of the pathogenic processes. Neurodegeneration, accompanied by reactive gliosis and astrocytosis is the common feature of most TREDs, which may suggest involvement of inflammation in pathogenesis. Indeed, a number of immune response markers have been observed in the blood and CNS of patients and mouse models, and the activation of these markers was even observed in the premanifest stage of the disease. Although inflammation is not an initiating factor of TREDs, growing evidence indicates that inflammatory responses involving astrocytes, microglia, and the peripheral immune system may contribute to disease progression. Herein, we review the involvement of the immune system in the pathogenesis of triplet repeat expansion diseases, with particular emphasis on polyglutamine disorders. We also present various therapeutic approaches targeting the dysregulated inflammation pathways in these diseases.
    Mediators of Inflammation 01/2015; 2015:1-11. DOI:10.1155/2015/873860 · 2.42 Impact Factor

Preview

Download
3 Downloads
Available from