At least nine neurodegenerative disorders-Huntington’s disease being perhaps the best known-are caused by the reiteration of glutamine-coding CAG trinucleotides in the genome. In huntingtin, ataxins, and other proteins, these repeats result in expanded polyglutamine tracts (PolyQ), which form nuclear inclusions. Whether aggregated or soluble monomeric polyQ proteins are the key pathogenic species is hotly debated (see related news item). One line of thought follows from the observation that polyQ protein inclusions sequester other, essential proteins, such as transcription factors (see related news item).

A report in the current PNAS early edition supports the idea that polyQ protein aggregation mediates cellular damage. Yaohui Chai and colleagues at Henry Paulson’s lab, University of Iowa, used exquisite, real-live imaging techniques to measure the diffusion of both mutant ataxin-3, which causes spinocerebellar ataxia type-3 or Machado-Joseph disease, and the transcription factor CBP (cAMP response element binding protein-binding protein), which has been identified in these nuclear inclusions. The authors expressed both proteins as green fluorescent protein (GFP) chimeras, which they photobleached in distinct cellular locations with a highly focused laser beam. The time it took unbleached chimeras to diffuse into this bleached zone after the laser was stopped (fluorescence recovery after photobleaching, or FRAP), and the rate at which fluorescence was lost during photobleaching (FLIP), revealed remarkable differences in protein mobility.

For example, normal ataxin-3, (28 glutamines), diffuses readily in the cytoplasm, and almost as fast in the nucleus. In contrast, mutant protein (84 glutamines) diffuses just as quickly in the cytoplasm as does wild type, but slows down markedly in the nucleus, and stays put in nuclear inclusions. CBP chimeras are freely diffusible when co-expressed with wild-type ataxin-3 but, in the presence of mutant ataxin-3, become trapped in nuclear inclusions.

The data support the idea that polyQ-expanded proteins sequester others. But the results also suggest that not all polyQ proteins are created equal. While CBP was sequestered by mutant ataxin-3 and mutant huntingtin, mutant ataxin-1 inclusions failed to retain the transcription factor, which freely diffused in and out of them.—Tom Fagan


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News Citations

  1. A New CAG Repeat Model Warns: Beware The Freely Floating Abnormal Protein!
  2. Transcriptional Activators Kidnapped by Huntingtin

Further Reading

Primary Papers

  1. . Live-cell imaging reveals divergent intracellular dynamics of polyglutamine disease proteins and supports a sequestration model of pathogenesis. Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9310-5. PubMed.