CAG tract of MJD-1 may be prone to frameshifts causing polyalanine accumulation
Claudia Gaspar,Merhdad Jannatipour,Patrick A. Dion,Janet Laganière,Jorge Sequeiros,Bernard Brais,Guy A. Rouleau +6 more
TLDR
It is proposed that transcriptional or translational frameshifts occurring within expanded CAG tracts result in the production and accumulation of polyalanine-containing mutant proteins and it is hypothesized that these alanine polymers deposit in cells forming INIs and may contribute to nuclear toxicity.Abstract:
Machado-Joseph disease (MJD) is one of several disorders caused by the expansion of a coding CAG repeat (exp-CAG). The presence of intranuclear inclusions (INIs) in patients and cellular models of exp-CAG-associated diseases has lead to a nuclear toxicity model. Similar INIs are found in oculopharyngeal muscular dystrophy, which is caused by a short expansion of an alanine-encoding GCG repeat. Here we propose that transcriptional or translational frameshifts occurring within expanded CAG tracts result in the production and accumulation of polyalanine-containing mutant proteins. We hypothesize that these alanine polymers deposit in cells forming INIs and may contribute to nuclear toxicity. We show evidence that supports our hypothesis in lymphoblast cells from MJD patients, as well as in pontine neurons of MJD brain and in in vitro cell culture models of the disease. We also provide evidence that alanine polymers alone are harmful to cells and predict that a similar pathogenic mechanism may occur in the other CAG repeat disorders.read more
Citations
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Comparative Genomics and Molecular Dynamics of DNA Repeats in Eukaryotes
TL;DR: The nature and distribution of dispersed and tandem repeats in eukaryotic genomes in the light of complete (or nearly complete) available genome sequences are described and a unified definition for mini- and microsatellites is proposed that takes into account their biological properties.
Journal ArticleDOI
Ribosomal frameshifting and transcriptional slippage: From genetic steganography and cryptography to adventitious use.
TL;DR: Together with dynamic codon redefinition, frameshifting is one of the forms of recoding that enriches gene expression and generates productively utilized products encoded trans-frame with respect to the genomic sequence.
Journal ArticleDOI
RAN Translation in Huntington Disease
Monica Banez-Coronel,Fatma Ayhan,Alex D. Tarabochia,Tao Zu,Barbara A. Perez,Solaleh Khoramian Tusi,Olga Pletnikova,David R. Borchelt,Christopher A. Ross,Russell L. Margolis,Anthony T. Yachnis,Juan C. Troncoso,Laura P.W. Ranum +12 more
TL;DR: Data suggest RAN proteins contribute to HD and that therapeutic strategies targeting both sense and antisense genes may be required for efficacy in HD patients, and suggests RAN translation may also contribute to other polyglutamine diseases.
Journal ArticleDOI
Oculopharyngeal muscular dystrophy.
TL;DR: Autosomal dominant oculopharyngeal muscular dystrophy is an adult-onset disease with worldwide distribution and unique intranuclear filament inclusions in skeletal muscle fibers are its morphological hallmark.
Journal ArticleDOI
The expanding biology of the C9orf72 nucleotide repeat expansion in neurodegenerative disease
TL;DR: A nucleotide repeat expansion within the chromosome 9 open reading frame 72 (C9orf72) gene was the first of this type of mutation to be linked to multiple neurological conditions, including amyotrophic lateral sclerosis and frontotemporal dementia.
References
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Journal ArticleDOI
Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the hd mutation
Stephen W. Davies,Mark Turmaine,Barbara A. Cozens,Marian DiFiglia,Alan H. Sharp,Christopher A. Ross,Eberhard Scherzinger,Erich E. Wanker,Laura Mangiarini,Gillian P. Bates +9 more
TL;DR: In this paper, the authors observed that mice transgenic for exon 1 of the human HD gene carrying (CAG)115 to 157 repeat expansions develop pronounced neuronal intranuclear inclusions, containing the proteins huntingtin and ubiquitin, prior to developing a neurological phenotype.
Journal ArticleDOI
Aggresomes: A Cellular Response to Misfolded Proteins
TL;DR: The intracellular fate of cystic fibrosis transmembrane conductance regulator (CFTR) is investigated and it is demonstrated that undegraded CFTR molecules accumulate at a distinct pericentriolar structure which is termed the aggresome.
Journal ArticleDOI
CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1
Yoshiya Kawaguchi,Toshihiro Okamoto,Masafumi Taniwaki,Megumi Aizawa,Miho Inoue,Sadao Katayama,Hideshi Kawakami,Shigenobu Nakamura,Masaki Nishimura,Ichiro Akiguchi,Jun Kimura,Shuh Narumiya,Akira Kakizuka +12 more
TL;DR: Southern blot analyses and genomic cloning demonstrates the existence of related genes, raising the possibility that similar abnormalities in related genes may give rise to diseases similar to Machado-Joseph disease.
Journal ArticleDOI
Huntingtin Acts in the Nucleus to Induce Apoptosis but Death Does Not Correlate with the Formation of Intranuclear Inclusions
Frédéric Saudou,Steven Finkbeiner,Steven Finkbeiner,Didier Devys,Michael E. Greenberg,Michael E. Greenberg +5 more
TL;DR: It is suggested that mutant huntingtin acts within the nucleus to induce neurodegeneration, however, intranuclear inclusions may reflect a cellular mechanism to protect against huntingtin-induced cell death.
Journal ArticleDOI
Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice.
Ivan A. Klement,Pamela J. Skinner,Michael D. Kaytor,Hong Yi,Steven M. Hersch,H. Brent Clark,Huda Y. Zoghbi,Harry T. Orr +7 more
TL;DR: Although nuclear localization of ataxin-1 is necessary, nuclear aggregation of atXS1 is not required to initiate pathogenesis in transgenic mice, demonstrating that nuclear localization is critical for pathogenesis.
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