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  • Title: Phosphorylation of presenilin-2 regulates its cleavage by caspases and retards progression of apoptosis.
    Author: Walter J, Schindzielorz A, Grünberg J, Haass C.
    Journal: Proc Natl Acad Sci U S A; 1999 Feb 16; 96(4):1391-6. PubMed ID: 9990034.
    Abstract:
    Mutations within the Presenilin-2 (PS-2) gene are associated with early onset familial Alzheimer's disease. The gene encodes a polytopic transmembrane protein that undergoes endoproteolytic processing resulting in the generation of N-terminal and C-terminal fragments (CTFs). PS-2 is also cleaved by proteases of the caspase family during apoptotic cell death. CTFs of PS-2 were shown to inhibit apoptosis, suggesting an important role in the regulation of programmed cell death. Recently, we found that the CTF of PS-2 is phosphorylated in vivo. We mapped the in vivo phosphorylation sites of PS-2 to serine residues 327 and 330, which are localized immediately adjacent to the cleavage sites of caspases after aspartate residues 326 and 329. Phosphorylation of PS-2 inhibits its cleavage by caspase-3. This effect can be mimicked by substitutions of serines 327 and 330 by aspartate or glutamate. In addition, the uncleavable form of PS-2 CTF was found to enhance its antiapoptotic properties, leading to a slower progression of apoptosis. These results demonstrate that PS-2 cleavage as well as its function in apoptosis can be regulated by protein phosphorylation. Alterations in the phosphorylation of PS-2 may therefore promote the pathogenesis of AD by affecting the susceptibility of neurons to apoptotic stimuli.
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