application): Protein aggregates, or cellular """"""""inclusions"""""""", are a prominent feature in a wide variety of neurodegenerative diseases, including Alzheimer's disease (AD). Proteasomal degradation appears to play a key role in removing aggregate prone molecules and submicroscopic aggregates, both of which can ultimately lead to visible inclusions. These investigators initially observed that cells stably expressing the N141I FAD mutant version of presenilin 2 (PS2) exhibited an increased tendency to form ubiquitin-positive aggregates consisting of misfolded PS2, as compared to cells expressing wild-type PS2. They have also found that capacitative Ca entry (CCE) was dramatically reduced by treatment with a proteasome inhibitor as well as by the N141I PS2 FAD mutation. CCE is a novel Ca entry mechanism that is induced by intracellular Ca pool depletion. These observations suggest a link between Ca dyshomeostasis and both proteasomal dysfunction and subsequent formation of protein aggregates. Consequently, they propose that conformational changes in the presenilins caused by FAD mutations promote misfolding and subsequent aggregation (e.g. submicroscopic aggregates), which would lead to Ca dyshomeostasis. Alternatively, mutant presenilins may first alter intracellular Ca homeostasis, which subsequently affects protein folding and proteasomal degradation. In either case, interplay between presenilin aggregates and perturbed Ca homeostasis (e.g. reduced CCE and depletion of the ER store) may contribute to other FAD-associated molecular phenotypes, such as increased AB42, by influencing protein trafficking or proteolytic processing. The overall goals will be to search for further evidence of proteasomal dysfunction in AD, to study the relationship between Ca signaling and protein aggregation, and to determine the underlying mechanism of how presenilin FAD mutations affect intracellular Ca homeostasis and proteasomal degradation.
| Sun, Yu; Yao, Jun; Kim, Tae-Wan et al. (2003) Expression of liver X receptor target genes decreases cellular amyloid beta peptide secretion. J Biol Chem 278:27688-94 |
| Yoo, A S; Cheng, I; Chung, S et al. (2000) Presenilin-mediated modulation of capacitative calcium entry. Neuron 27:561-72 |
