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Trinucleotide repeats and neurodegenerative disease

Everett, CM; Wood, NW; (2004) Trinucleotide repeats and neurodegenerative disease. BRAIN , 127 2385 - 2405. 10.1093/brain/awh278.

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Abstract

Major insights have been attained into the molecular pathology of the trinucleotide repeat neurodegenerative diseases over the past decade. Genetic definition has allowed subclassification into translated polyglutamine diseases, which are due to CAG repeat expansions, and a more heterogeneous group in which the trinucleotide repeat remains untranslated. The polyglutamine disorders are due to a toxic gain of function of mutant expanded proteins. Neuronal intranuclear inclusions (NIIs) characteristically occur. Protein misfolding, interference with DNA transcription and RNA processing, activation of apoptosis and dysfunction of cytoplasmic elements have all been invoked in the toxic process. The end result is apoptotic cell death with many aspects of neuronal function being perturbed. Promising progress has been made into arresting and reversing neurodegeneration in both cellular and animal models. The molecular mechanisms underlying the untranslated group remain less clear. Impedance of gene transcription secondary to abnormal DNA structures formed by repeats, modification of chromatin gene packaging and dysfunction at the RNA level have all been suggested as possible pathological mechanisms. These diseases remain irreversible. It is hoped that clarification of the molecular pathogenic mechanisms will provide the tools for future therapeutic intervention.

Type: Article
Title: Trinucleotide repeats and neurodegenerative disease
DOI: 10.1093/brain/awh278
Keywords: trinucleotide repeat, polyglutamine expansion, neuronal intranuclear inclusion, transcription factors, chromatin, DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY, BULBAR MUSCULAR-ATROPHY, MACHADO-JOSEPH-DISEASE, DOMINANT CEREBELLAR-ATAXIA, KNOCK-IN MICE, NEURONAL INTRANUCLEAR INCLUSIONS, ANDROGEN RECEPTOR PROTEIN, CREB-BINDING PROTEIN, EXPANDED CAG REPEAT, DOT-TTC REPEATS
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
URI: http://discovery.ucl.ac.uk/id/eprint/140118
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