Current Medicinal Chemistry

Atta-ur-Rahman, FRS
Honorary Life Fellow
Kings College
University of Cambridge
Cambridge
UK

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Towards the Treatment of Polyglutamine Diseases: The Modulatory Role of Protein Context

Author(s): A. L. Robertson, S. P. Bottomley.

Abstract:

Protein aggregation is a key mechanism involved in neurodegeneration associated with Alzheimers, Parkinsons and Huntingtons diseases. Nine diseases (including Huntingtons) 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 polyQ regions form fibrillar aggregates and the properties of these aggregates. In this review we consider the role of protein context in modulating the polyQ diseases and the therapeutic potential of targeting non-polyQ protein properties.

Keywords: Polyglutamine, protein aggregation, protein structure, misfolding, multidomain aggregation, flanking domains

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Article Details

VOLUME: 17
ISSUE: 27
Year: 2010
Page: [3058 - 3068]
Pages: 11
DOI: 10.2174/092986710791959800
Price: $58