Glycogen synthase kinase-3 beta regulates presenilin 1 C-terminal fragmentlevels

The majority of familial Alzheimer's disease cases have been attributed to mutations in the presenilin 1 (PSI) gene. PSI is synthesized as an inactive holoprotein that undergoes endoproteolytic processing to generate a functi onal N- and C-terminal heterodimer (NTF and CTF, respectively). We identifi ed a single residue in PSI, Ser(397), which regulates the CTF levels in a p opulation of dimer that has a rapid turnover. This residue is part of a hig hly conserved glycogen synthase kinase-3 beta (GSK-3 beta) consensus phosph orylation site within the loop domain of PSI. Site-directed mutagenesis at the Ser(397) position increased levels of PSI CTF but not NTF or holoprotei n. Similar increases in only CTF levels were seen when cells expressing wil d type PSI were treated with lithium chloride, an inhibitor of GSK-3 beta. Both wild type and PSI S397A CTF displayed a biphasic turnover, reflecting rapidly degraded and stable populations. Rapid turnover was delayed for mut ant PSI S397A, causing increased CTF. These data demonstrate that PSI NTF-C TF endoproteolytic fragments are generated in excess, that phosphorylation at Ser(397) by GSK-3 beta regulates the discard of excess CTF, and that the disposal of surplus NTF is mediated by an independent mechanism. Overall, the results indicate that production of active NTF-CTF dimer is more comple x than limited endoproteolysis of PSI holoprotein and instead involves addi tional regulatory events.