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      Trinucleotide Repeat Disorders

      1 , 2

      Annual Review of Neuroscience

      Annual Reviews

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          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.

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          Most cited references 290

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          Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases.

          Many lines of evidence suggest that mitochondria have a central role in ageing-related neurodegenerative diseases. Mitochondria are critical regulators of cell death, a key feature of neurodegeneration. Mutations in mitochondrial DNA and oxidative stress both contribute to ageing, which is the greatest risk factor for neurodegenerative diseases. In all major examples of these diseases there is strong evidence that mitochondrial dysfunction occurs early and acts causally in disease pathogenesis. Moreover, an impressive number of disease-specific proteins interact with mitochondria. Thus, therapies targeting basic mitochondrial processes, such as energy metabolism or free-radical generation, or specific interactions of disease-related proteins with mitochondria, hold great promise.
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            Mechanisms of alternative pre-messenger RNA splicing.

             Justin Black (2002)
            Alternative pre-mRNA splicing is a central mode of genetic regulation in higher eukaryotes. Variability in splicing patterns is a major source of protein diversity from the genome. In this review, I describe what is currently known of the molecular mechanisms that control changes in splice site choice. I start with the best-characterized systems from the Drosophila sex determination pathway, and then describe the regulators of other systems about whose mechanisms there is some data. How these regulators are combined into complex systems of tissue-specific splicing is discussed. In conclusion, very recent studies are presented that point to new directions for understanding alternative splicing and its mechanisms.
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              Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice.

              Huntington's disease (HD) is one of an increasing number of neurodegenerative disorders caused by a CAG/polyglutamine repeat expansion. Mice have been generated that are transgenic for the 5' end of the human HD gene carrying (CAG)115-(CAG)150 repeat expansions. In three lines, the transgene is ubiquitously expressed at both mRNA and protein level. Transgenic mice exhibit a progressive neurological phenotype that exhibits many of the features of HD, including choreiform-like movements, involuntary stereotypic movements, tremor, and epileptic seizures, as well as nonmovement disorder components. This transgenic model will greatly assist in an eventual understanding of the molecular pathology of HD and may open the way to the testing of intervention strategies.
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                Author and article information

                Journal
                Annual Review of Neuroscience
                Annu. Rev. Neurosci.
                Annual Reviews
                0147-006X
                1545-4126
                July 2007
                July 2007
                : 30
                : 1
                : 575-621
                Affiliations
                [1 ]Institute of Human Genetics, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, 55455; email:
                [2 ]Departments of Pediatrics, Molecular and Human Genetics, Neurology, and Neuroscience, Baylor College of Medicine, and Howard Hughes Medical Institute, Houston, Texas 77030; email:
                Article
                10.1146/annurev.neuro.29.051605.113042
                17417937
                © 2007

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