Tightly associated factors (TAFs) play an essential role in transcriptional activation through their interaction with a variety of activators. TAF[II]135 (a.k.a. TAF[II]130) is a human homologue of Drosophila TAF[II]110, the first TAF shown to have coactivator activity. TAF[II]135 contains multiple glutamine-rich regions, as well as a coactivator domain (CAD). The glutamine-rich regions of TAF[II]135 facilitate interaction with Sp1 and CREB, which leads to enhancement of both Sp1- and CREB-mediated transcription. In addition, TAF[II]135 can potentiate transcriptional stimulation by AF-2 of the retinoic acid, thyroid hormone, and vitamine D3 receptors. However, TAF[II]135 does not interact with the AF-2s of the estrogen and retinoid X receptors. Interestingly, TAF[II]135 enhancement of CREB transcriptional activity may be disrupted by expanded polyglutamine (CAG) repeats found in at least eight different neurodegenerative disorders. Thus, TAF[II]135 may have important coactivator activities in many different transcription-regulating cell signaling pathways, and interference of TAF[II]135 activity by CAG repeats may be a common mechanism of specific types of neuropathologies.