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Pathogenic mechanisms
A01 Molecular mechanisms underlying polyglutamine length influence on huntingtin interactions
  1. A Davranche1,
  2. F Klein1,
  3. D Altschuh2,
  4. G Zeder-Lutz2,
  5. C Weber1,
  6. Y Trottier1
  1. 1IGBMC, Illkirch, France
  2. 2ESBS, Boulevard Sébastien Brant, Illkirch, France

Abstract

Background Huntington's disease (HD) is due to an expansion above a polyQ length threshold in the huntingtin (Htt) protein. This expansion confers a toxic gain of function to the Htt which relies on its malfunction and propensity to misfold and aggregate. A first model proposed to explain this polyQ length dependent toxicity threshold stated that it is triggered by a toxic conformational change that occurs only above a certain polyQ length. However, we and others showed that normal and expanded polyQ display strikingly similar structural properties, supporting another model in which polyQ tracts are inherently toxic sequences whose deleterious effect gradually increases with polyQ length and aggregation kinetics. In this model, polyQ toxicity manifests when cellular factors that prevent proteotoxicity are overwhelmed.

Aims Hundreds of proteins have been found to interact with Htt and many of them showed increased or decreased affinity with mutant Htt. If small and expanded polyQ share similar structural properties, what are the molecular mechanisms underlying these dysinteractions? The question has therapeutic implication, as the specificity of neuronal vulnerability in HD is thought to be due, in part, to mutant Htt dysinteractions with protein partners.

Methods Up to now, the polyQ length influence on Htt interactions was exclusively studied using semiquantitative techniques prone to be biased by polyQ aggregation (Y2H, IP and pull downs). We report the first precise quantification of the polyQ length influence on Htt/partners affinity, using a dedicated biophysical technique (surface plasmon resonance), in conditions where the absence of aggregation is strictly controlled.

Results In conditions where the absence of aggregates is strictly controlled, we observe that polyQ length variations do not affect the interactions between soluble Htt exon-1 and protein partners. However, we provide evidence that the presence of aggregated polyQ species can dramatically influence the behaviour of Htt partners.

Conclusions We thus propose that aggregated polyQ species influence Htt's and its partners' behaviours and result in aberrant interactions. Our work suggests that modulating mutant Htt aggregation could have positive effects on specific cellular pathways deregulated in HD.

  • aberrant Htt interactions
  • aggregation
  • affinity

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