At least nine neurodegenerative diseases are caused by mutant proteins containing expanded polyglutamine (PG) repeats, which form intracellular aggregates and are neurotoxic. Recent investigations have indicated that the source of this neurotoxicity may lie in the capacity of the PG repeats to disrupt the transcriptional machinery.
Additional support for this hypothesis is provided by new research with fruit fly, yeast, and mammalian cell culture models of neurodegeneration, which shows that expanded PG repeats alter histone acetylation, a protein modification that plays a key role in transcriptional regulation. Experiments by Steffan et al. revealed that, through direct binding, the expanded PG repeats inhibit the enzymatic activity of acetyltransferases involved in histone acetylation, and that when expressed in a neuronal cell line, these repeats reduce the level of histone acetylation. Consistent with this, Hughes et al. found that expression of expanded PG repeats in yeast shifted the pattern of transcribed genes to a pattern characteristic of mutant yeast strains with defects in histone acetylation. Finally, in a study of cultured mammalian neurons, McCampbell et al. found that targeting of expanded PG repeats to the nucleus caused cell death that was associated with decreased histone acetylation and that could be mitigated by overexpression of the histone acetyltransferase CBP.
In all cases--and most significantly in the fruit fly models of neurodegeneration studied by Steffan et al.--PG toxicity could be slowed or prevented by treatment with small-molecule histone deacetylase inhibitors. Thus, these drugs, which already are in clinical trials for other disorders, could have therapeutic potential for neurodegenerative diseases. -- PAK
Nature 413, 739 (2001); Proc. Natl. Acad. Sci. U.S.A. 98, 13201; 15179 (2001).
