Joan Steffan, working with Leslie Thompson at University of California, Irvine, and colleagues elsewhere, report that the poly-Q containing peptide directly binds to the acetyltransferase domain of the proteins CREB-binding protein (CBP) and p300/CBP-associated factor (P/CAF). Both these proteins are general transcription factors, and they add acetyl groups to histone proteins strung around DNA like a beaded necklace. Generally speaking, acetyl transferases increase gene transcription and occur in a balance with opposing histone deacetylases.

The authors reasoned that if poly-Q's inhibition of histone acetylation was pathogenic, then lowering histone deacetylation accordingly should be therapeutic. They fed a diet laden with pharmacological histone deacetylase inhibitors to poly-Q-expressing mutant Drosophila and found the inhibitors indeed slowed neurodegeneration of the flies' compound eyes and increased the animals' shortened life span. Some of the inhibitors used in this study are either FDA-approved or in phase-1 clinical trials for cancer (Marks et al., Richon et al.).

"It seems strange that the impairment of transcription factors expressed from early development throughout an embryo can cause adult-onset diseases that affect only neurons. But concerns about the validity of the findings should be laid to rest by the discovery that a polyglutamine expansion in a key transcription factor, TBP, directly causes a nerve-cell-specific disease, spinocerebellar ataxia 17 (Nakamura K et al.)", writes Gillian Bates at Guy's Hospital London in an accompanying News and Views article.-Gabrielle Strobel.

Reference:Steffan JS, Bodai L, Pallos J, Poelman M, McCampbell A, Apostol BL, Kazantsev A, Schmidt E, Zhu YZ, Greenwald M, Kurokawa R, Housman DE, Jackson GR, Marsh JL, Thompson LM. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature. 2001 Oct 18;413(6857):739-43. Abstract