| MPA4 | |
| Project ID |  MPA4 [Protein] |
| Project Theme | Structural analysis of γ-secretase complex for the development of the treatment for Alzheimer's disease |
| Project Theme (short) | Alzheimer's disease: γ-secretase |
| Principal Investigator | Taisuke Tomita |
| Affiliation | Graduate School of Pharmaceutical Sciences, The University of Tokyo |
| Backgrounds | - Alzheimer's diseaseis caused by amyloid beta(Aβ) deposits - Aβ is a peptide fragment cleaved from a larger protein called amyloid precursor protein(APP) and γ-secretase functions in the final stage of the cleavage - γ-secretase is an integral membrane protein and a protease complex consisting of four individual proteins (presenilin, nicastrin, APH-1 and PEN-2), which has hampered its structural analyses |
| Highlights | - We have succeeded in producing and purifying both the entire γ-secretase complex and the ectodomain of nicastrin - We have identified novel compounds that inhibit γ-secretase activity without repressing Notch signaling |
| Outline | Alzheimer's disease is caused by amyloid beta (Aβ) deposits. Aβ is a peptide fragment cleaved from a larger protein called amyloid precursor protein (APP) and γ-secretase functions in the final stage of the cleavage. γ-secretase is an integral membrane protein and a protease complex consisting of four individual proteins (presenilin, nicastrin, APH-1 and PEN-2), which has hampered its structural analyses. We will use single-particle image analysis to build up a three dimensional reconstruction of the entire γ-secretase comlex, while X-ray crystallography is employed to determine the structure of nicastrin, a component of γ-secretase, which recognizes substrates. We are screening compounds and antibodies that regulate the activity of γ-secretase. Patents are pending for some of them. We would like to elucidate the relationship between the structure and activity of γ-secretase by utilizing our original compounds. |
| Review | ACS Chem. Biol. J. Biol. Chem. J. Am. Chem. Soc. J. Neurosci. Bioorg. Med. Chem. Lett. |
| CSML File | MPA4.csml |