Tissue transglutaminase (tTG) catalyzes the incorporation of polyamines into substrates, or the formation of isopeptide bonds. tTG also binds and hydrolyzes GTP/ATP. Huntington's disease (HD) is caused by a pathological expansion of the polyglutamine domain in the protein huntingtin (htt). Because a polypeptide bound Gln residue is the primary determining factor for a tTG substrate, it has been hypothesized that due to the increase in Gln content, mutant htt may modified by tTG and this event may contribute to the pathogenesis of HD, possibly by facilitating the formation of htt aggregates. tTG is increased in HD, suggesting involvement in the pathogenic process. However, tTG is not required for aggregate formation. Further, tTG is excluded from htt aggregates and increasing or decreasing tTG has no effect on the frequency or localization of the aggregates. Considering these and other data, tTG is unlikely to play a major role in the formation of htt inclusions in HD brain. tTG may play a role in modulating neuronal cell death in response to specific stressors. If a stress increases the transamidating activity of tTG (e.g. increases in Ca++ levels), then tTG facilitates the cell death process. In contrast, if a stress does not result in an increase in the transamidating activity of tTG, then tTG protects against cell death. The protective effects of tTG are independent of its transamidating and hence likely dependent on its GTP/ATP binding and hydrolytic activity. Therefore the increase in tTG levels in HD brain could either be helpful or harmful depending on the cellular mechanisms that contribute to neuronal death.Acknowledgements: Supported by NIH grant AG12396.