Sama F Sleiman, Brett C Langley, Manuela Basso, Jill Berlin, Li Xia, Jimmy B Payappilly, Madan K Kharel, Hengchang Guo, J Lawrence Marsh, Leslie Michels Thompson, Lata Mahishi, Preeti Ahuja, W Robb MacLellan, Daniel H Geschwind, Giovanni Coppola, Jürgen Rohr, Rajiv R Ratan
Oncogenic transformation of postmitotic neurons triggers cell death, but the identity of genes critical for degeneration remain unclear. The antitumor antibiotic mithramycin prolongs survival of mouse models of Huntington's disease in vivo and inhibits oxidative stress-induced death in cortical neurons in vitro. We had correlated protection by mithramycin with its ability to bind to GC-rich DNA and globally displace Sp1 family transcription factors. To understand how antitumor drugs prevent neurodegeneration, here we use structure-activity relationships of mithramycin analogs to discover that selective DNA-binding inhibition of the drug is necessary for its neuroprotective effect...
May 4, 2011: Journal of Neuroscience