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RNA repeat expansions cause a host of incurable, genetically-defined diseases. The most common class of RNA repeats are trinucleotide repeats. These long, repeating transcripts fold into hairpins containing 1 × 1 internal loops that can mediate disease via a variety of mechanism(s) in which RNA is the central player. Two of these disorders are Huntington's disease and myotonic dystrophy type 1, which are caused by r(CAG) and r(CUG) repeats, respectively. We report the structures of two RNA constructs containing three copies of a r(CAG) [r(3×CAG)] or r(CUG) [r(3×CUG)] motif that were modeled with nuclear magnetic resonance spectroscopy and simulated annealing with restrained molecular dynamics. The 1 × 1 internal loops of r(3×CAG) are stabilized by one hydrogen bond (cis Watson-Crick/Watson-Crick) AA pairs while those of r(3×CUG) prefer one or two hydrogen bond (cis Watson-Crick/Watson-Crick) UU pairs. Assigned chemical shifts for the residues depended on the identity of neighbors or next nearest neighbors. Additional insights into the dynamics of these RNA constructs were gained by molecular dynamics simulations and a discrete path sampling method. Results indicate that the global structures of the RNA are A-form, and that the loop regions are dynamic. The results will be useful to understand the dynamic trajectory of these RNA repeats but also may aid in the development of therapeutics.
This article was published in the following journal.
Huntington's disease is a rare, neurodegenerative disease caused by an expanded CAG repeat mutation in the huntingtin gene. Compared with adult-onset Huntington's disease, juvenile Huntington's diseas...
The Fragile X-related disorders (FXDs) are members of a large group of human neurological or neurodevelopmental conditions known as the Repeat Expansion Diseases. The mutation responsible for all of t...
Lowering the levels of disease-causing proteins is an attractive treatment strategy for neurodegenerative disorders, among which Huntington's disease is an appealing disease for testing this strategy ...
Expansions of polygutamine-encoding stretches in several genes cause neurodegenerative disorders including Huntington's Disease and Spinocerebellar Ataxia type 3. Expression of the human disease allel...
We aimed to assess whether differences in energy metabolism in fibroblast cell lines derived from patients with Huntington disease were associated with age at onset independent of the cytosine-adenine...
The purpose of this trial is to study early brain and behavioral changes in people who have the gene expansion for Huntington's disease, but are currently healthy and have no symptoms.
The principal means of measuring motor impairment in Huntington disease (HD) is the Unified Huntington's Disease Rating Scale (UHDRS) total motor score, which is subjective, categorical, r...
This study is being conducted to determine the safety and tolerability of Dimebon in people with Huntington's disease after short-term exposure (one week) and after longer exposure (three ...
The purpose of this study is to know the limits of feasibility of a reliable oculomotor record for patient with Huntington's disease.
The purpose of this study is to define the natural history and experiences of people who are at risk for developing Huntington's disease but who do not know their genetic status.
Membrane glycosylphosphatidylinositol-anchored glycoproteins that may aggregate into rod-like structures. The prion protein (PRNP) gene is characterized by five TANDEM REPEAT SEQUENCES that encode a highly unstable protein region of five octapeptide repeats. Mutations in the repeat region and elsewhere in this gene are associated with CREUTZFELDT-JAKOB DISEASE; FATAL FAMILIAL INSOMNIA; GERSTMANN-STRAUSSLER DISEASE; Huntington disease-like 1, and KURU.
A biochemical phenomenon in which misfolded proteins aggregate either intra- or extracellularly. Triggered by factors such as MUTATION, POST-TRANSLATIONAL MODIFICATIONS, and environmental stress, it is generally associated with ALZHEIMER DISEASE; PARKINSON DISEASE; HUNTINGTON DISEASE; and TYPE 2 DIABETES MELLITUS.
A protein that is highly expressed in the nervous system as well as other tissues; its size and structure vary due to polymorphisms. Expanded CAG TRINUCLEOTIDE REPEATS have been identified in the Huntingtin (HD) Gene of patients with HUNTINGTON DISEASE and are associated with abnormal PROTEIN AGGREGATES. Huntingtin interacts with proteins involved in a variety of gene expression and cellular processes; it is also essential for embryonic development.
A spectrum of disorders characterized by clonal expansions of the peripheral blood LYMPHOCYTE populations known as large granular lymphocytes which contain abundant cytoplasm and azurophilic granules. Subtypes develop from either CD3-negative NATURAL KILLER CELLS or CD3-positive T-CELLS. The clinical course of both subtypes can vary from spontaneous regression to progressive, malignant disease.
A repeat operation for the same condition in the same patient due to disease progression or recurrence, or as followup to failed previous surgery.
Huntington's disease is a hereditary disease caused by a defect in a single gene on Chromosome 4 that is inherited in an autosomal dominant fashion. The defect causes a part of DNA, called a CAG repeat, to occur many more times than it is supposed to...
Muscular dystrophy is a group of degenerative inherited disorders causing muscle weakness and loss of muscle tissue. The different types are Becker muscular dystrophy, Duchenne muscular dystrophy, Emery-Dreifuss muscular dystrophy, Facioscapulohumeral mu...