Expansion of unstable CAG repeat encoding homopolymeric polyglutamine stretch (polyQ) is a distinctive common molecular feature of dominantly inherited polyQ diseases. Using a powerful approach that enables us to measure the thermodynamic stability directly in the cell, we show that expansion of the glutamine stretch destabilizes the huntingtin exon 1 in a length-dependent manner thus increasing its propensity to aggregate. Three organic osmolytes, proline, TMAO and glycine-betaine, counteract the destabilization effect of the polyQ expansion and alter the aggregation pathway of the pathologic huntingtin exon 1 fragment. Whereas TMAO and proline redirect amyloid fibrillogenesis to non-amyloidogenic assemblies via two dissimilar molecular mechanisms, glycine-betaine enhances fibrillization in a fashion reminiscent of the genesis of the functional amyloids. Using further structural approaches, both in ensemble and in a single-molecule mode, we provide a molecular explanation for thevariations in the mechanisms of action of different osmolytes.

Natural osmoprotective substances modulate the stability and aggregation pathway of polyglutamine proteins

241st National Meeting (2011)

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