Towards the treatment of polyglutamine diseases: the modulatory role of protein context

Current Medicinal Chemistry
Amy L Robertson, Stephen P Bottomley

Abstract

Protein aggregation is a key mechanism involved in neurodegeneration associated with Alzheimer's, Parkinson's and Huntington's diseases. Nine diseases (including Huntington's) arise from polyglutamine (polyQ) expansion above a repeat threshold of approximately 37 glutamines, and neuronal toxicity correlates with the process of protein aggregation. The similar toxic gain-of-function mechanism of the nine diseases supports the hypothesis that disease onset and progression is dependent upon polyQ expansion. However, there is an increasing body of literature demonstrating that the protein context of the polyQ tract has an essential role in the disease process. The composition of regions flanking repeats can alter the biochemical and biophysical properties of the polyQ region. A number of the disease proteins are proteolytically cleaved, with release of the polyQ-containing fragment initiating aggregation. Interactions of flanking domains with other molecules can also influence aggregation and cellular localization, which are critical factors for toxicity. More recently, there is evidence that domains flanking the polyQ tract can also aggregate independent of the polyQ tract, and that this significantly alters the rate at which the ...Continue Reading

Citations

Mar 9, 2011·Journal of the American Chemical Society·V N SivanandamPatrick C A van der Wel
Nov 10, 2010·Nucleic Acids Research·Amy L RobertsonAshley M Buckle
Jul 31, 2013·PloS One·Helen M SaundersStephen P Bottomley
Dec 12, 2012·Trends in Cell Biology·Elyse S BlumShai Shaham
Jul 12, 2011·Progress in Neurobiology·Carlos A MatosAna Luísa Carvalho
Feb 16, 2012·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·László Bodai, J Lawrence Marsh
Jul 23, 2011·Protein Science : a Publication of the Protein Society·Helen M SaundersStephen P Bottomley
Dec 10, 2014·Biochimica Et Biophysica Acta·Céline HuynenMireille Dumoulin
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