Expanded polyQ SCAs

These SCAs are caused by an expansion in the number of CAG repeats which results in coding for excess glutamine (abbreviated as Q) in the affected protein. These SCAs are therefore called expanded polyglutamine, or polyQ SCAs.

All proteins fold into a unique 3D shape, however research shows that the CAG expansions in these SCAs cause misfolding of the protein and change its unique shape. This causes the proteins to ‘clump together’, a process known as aggregation (Soong & Paulson, 2007). These aggregates then form clusters known as inclusions within the cells both in the central body (nucleus) and the cell fluid (cytoplasm) (Ross & Poirier, 2004).

The aggregation and deposition of these misfolded proteins is believed to lead to nerve cells functioning incorrectly and eventually dying (Dueñas et al, 2006).

Another possible mechanism being looked at is the process by which genes are converted into proteins (gene transcription) as this is believed to be upset in polyglutamine conditions. For example, histone acetylation, which is part of gene transcription, is reduced in a cell model of Huntington’s disease, a polyglutamine disorder. One way of restoring this is to inhibit the histone de-acetylase (HDAC) enzymes using an HDAC inhibitor. Promising results have been seen with this approach in cell and fly models of Huntington’s disease, suggesting that HDAC inhibitors may also be of benefit in SCA (McCampbell et al, 2001; Steffan et al, 2001).

Ataxia UK is helping to fund a research project led by Professor Pastore and Dr Giunti at the National Institute for Medical Research in London which began in 2008 and is looking into the role of CAA interruptions in polyglutamine disorders. Click here for details.

Although more still needs to be learnt about the molecular basis of SCAs, new insights into the toxic protein mechanism in these expanded polyglutamine SCAs have begun to suggest routes to preventative therapy (Soong & Paulson, 2007).

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Expanded polyQ SCAs