Polyglutamine (poly Q) expansion in the huntingtin protein (htt) causes Huntington's disease (HD), yet it remains unclear clear how this expansion induces the cellular and neurological damage of the disease. Hints have come from the identification of molecular partners of htt, such as the huntingtin-interacting protein (Hip1), and huntingtin-associated protein (see related news item), but the search continues for more pieces to the puzzle. In the 18 February Nature Cell Biology online, Crislyn D'Souza-Shorey, University of Notre Dame, Indiana, and coworkers, report the identification of another htt partner that may be involved in the etiology of HD.

The authors expressed the ADP ribosylation factor (ARF)-interacting protein, arfaptin 2, in cultured Chinese hamster ovary cells and found that it formed aggregates with an uncanny resemblance to the inclusion bodies seen in Huntington neurons. Htt and arfaptin 2 colocalized to these nuclear and centriolar aggregates, whereas htt resides in caveolae in wild-type cells. Furthermore, when a polyQ-expanded exon 1 of htt was expressed in the PC12 neuronal cell line, it colocalized with endogenous arfaptin 2. In vivo, the researchers found arfaptin 2 ubiquitously expressed throughout the cytosol of mouse brain, but in R6/2 mice expressing polyQ-expanded human huntingtin, arfaptin 2 appeared in regions of htt aggregation.

The authors found that expression of arfaptin 2 increased htt aggregation in PC12 cells, but co-expression of a dominant-negative mutant actually inhibited aggregation. An inhibitor of the 26S proteasome blocks this effect, implicating arfaptin in the ubiquitin-proteasome system. Further in-vitro data strengthened this proteasome link.—Tom Fagan

Comments

Make a Comment

To make a comment you must login or register.

Comments on this content

No Available Comments

References

News Citations

  1. Protein-Protein Interactions, Cytoskeleton Implicated in Huntington's

Further Reading

Primary Papers

  1. . Arfaptin 2 regulates the aggregation of mutant huntingtin protein. Nat Cell Biol. 2002 Mar;4(3):240-5. PubMed.