Attenuation of inhibitory PAS domain protein-induced cell death by synthetic peptides derived from Mcl-1 transmenbrane domain.

Expression of Inhibitory PAS domain protein (IPAS) induces apoptosis by inhibiting the anti-apoptotic activity of mitochondrial pro-survival proteins including Bcl-xL and Mcl-1 through direct binding. Analysis to examine the IPAS-binding region in Bcl-xL demonstrated that the C-terminal transmembrane (TM) domain is indispensable for the specific binding. A chimeric protein composed of the TM domain of Mcl-1 fused to the C-terminus of Citrine also exhibited a binding affinity to IPAS, and markedly attenuated apoptosis caused by the overexpression of Cerulean-IPAS in SH-SY5Y cells. HIV-1 TAT cell-penetrating peptide-conjugated synthetic peptides that cover whole or parts of the Mcl-1 TM domain showed anti-apoptotic activity in the CoCl2-induced cell death in PC12 cells. Administration of these highly effective anti-apoptotic peptides to mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that produces a reliable mouse model of Parkinson's disease (PD) decreased neuronal cell loss in the substantia nigra pars compacta. Therefore, the peptides may be considered promising therapeutic agents for neurodegenerative disorders such as PD and stroke.