Abstract
Nicastrin and presenilin are two major components of the gamma-secretase complex, which executes the intramembrane proteolysis of type I integral membrane proteins such as the amyloid precursor protein (APP) and Notch. Nicastrin is synthesized in fibroblasts and neurons as an endoglycosidase-H-sensitive glycosylated precursor protein (immature nicastrin) and is then modified by complex glycosylation in the Golgi apparatus and by sialylation in the trans-Golgi network (mature nicastrin). These modifications are not observed with exogenously overexpressed nicastrin. Under normal cell culture conditions, only mature nicastrin is expressed at the cell surface and binds to the presenilin heterodimers. Mature nicastrin has a half-life of more than 24 hours. In the absence of presenilin 1 and 2, nicastrin remains entirely endoglycosidase H sensitive, is retained in the endoplasmic reticulum and is slowly degraded. Single presenilin 1 or presenilin 2 deficiency affects glycosylation of nicastrin to a lesser extent than the combined presenilin deficiencies, suggesting a correlation between either the transport of nicastrin out of the endoplasmic reticulum or the concomitant complex glycosylation of nicastrin, and gamma-secretase activity. However, when complex glycosylation of nicastrin was inhibited using mannosidase I inhibitors, gamma-secretase cleavage of APP or Notch was not inhibited and the immature nicastrin still associates with presenilin and appears at the cell surface. Complex glycosylation of nicastrin is therefore not needed for gamma-secretase activity. Because the trafficking of nicastrin to the Golgi apparatus is dependent on presenilins, our data point to a central role of presenilin in nicastrin maturation/localization, which could help to partially resolve the 'spatial paradox'.
Highlights
Introduction γSecretase activity is responsible for the cleavage of the transmembrane domain of the amyloid precursor protein (APP), releasing the amyloid peptide Aβ and the APP intracellular domain
Nicastrin and presenilin are two major components of the γ-secretase complex, which executes the intramembrane proteolysis of type I integral membrane proteins such as the amyloid precursor protein (APP) and Notch
Nicastrin is synthesized in fibroblasts and neurons as an endoglycosidase-H-sensitive glycosylated precursor protein and is modified by complex glycosylation in the Golgi apparatus and by sialylation in the trans-Golgi network
Summary
Introduction γSecretase activity is responsible for the cleavage of the transmembrane domain of the amyloid precursor protein (APP), releasing the amyloid peptide Aβ and the APP intracellular domain. The γ-secretase molecular machinery consists at least of presenilins (PSs) (Herreman et al, 2000; Zhang et al, 2000), nicastrin (Chung and Struhl, 2001; Hu et al, 2002; Lopez-Schier and St Johnston, 2002; Yu et al, 2000), pen-2 (Francis et al, 2002; Steiner et al, 2002) and the aph proteins (Francis et al, 2002; Goutte et al, 2002) It has been the subject of intense research because of its therapeutic potential for Alzheimer’s disease, and because of the wide variety of biological processes in which regulated intramembrane proteolysis by γsecretase has been implicated (Annaert and De Strooper, 2002; Kopan and Goate, 2000; Selkoe, 1999; Sisodia and St GeorgeHyslop, 2002; Steiner and Haass, 2000). It is possible that γ-secretase is involved in the release and disassembly of the
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